Secreted and transmembrane polypeptides and nucleic acids encoding the same

ABSTRACT

The present invention is directed to novel polypeptides and to nucleic acid molecules encoding those polypeptides. Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention.

FIELD OF THE INVENTION

[0001] The present invention relates generally to the identification andisolation of novel DNA and to the recombinant production of novelpolypeptides encoded by that DNA.

BACKGROUND OF THE INVENTION

[0002] Extracellular proteins play an important role in the formation,differentiation and maintenance of multicellular organisms. The fate ofmany individual cells, e.g., proliferation, migration, differentiation,or interaction with other cells, is typically governed by informationreceived from other cells and/or the immediate environment. Thisinformation is often transmitted by secreted polypeptides (for instance,mitogenic factors, survival factors, cytotoxic factors, differentiationfactors, neuropeptides, and hormones) which are, in turn, received andinterpreted by diverse cell receptors or membrane-bound proteins. Thesesecreted polypeptides or signaling molecules normally pass through thecellular secretory pathway to reach their site of action in theextracellular environment.

[0003] Secreted proteins have various industrial applications, includingpharmaceuticals, diagnostics, biosensors and bioreactors. Most proteindrugs available at present, such as thrombolytic agents, interferons,interleukins, erythropoietins, colony stimulating factors, and variousother cytokines, are secretory proteins. Their receptors, which aremembrane proteins, also have potential .as therapeutic or diagnosticagents. Efforts are being undertaken by both industry and academia toidentify new, native secreted proteins. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel secreted proteins. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)].

[0004] Membrane-bound proteins and receptors can play an important rolein the formation, differentiation and maintenance of multicellularorganisms. The fate of many individual cells, e.g., proliferation,migration, differentiation, or interaction with other cells, istypically governed by information received from other cells and/or theimmediate environment. This information is often transmitted by secretedpolypeptides (for instance, mitogenic factors, survival factors,cytotoxic factors, differentiation factors, neuropeptides, and honnones)which are, in turn, received and interpreted by diverse cell receptorsor membrane-bound proteins. Such membrane-bound proteins and cellreceptors include, but are not limited to, cytokine receptors, receptorkinases, receptor phosphatases, receptors involved in cell-cellinteractions, and cellular adhesin molecules like selectins andintegrins. For instance, transduction of signals that regulate cellgrowth and differentiation is regulated in part by phosphorylation ofvarious cellular proteins. Protein tyrosine kinases, enzymes thatcatalyze that process, can also act as growth factor receptors. Examplesinclude fibroblast growth factor receptor and nerve growth factorreceptor.

[0005] Membrane-bound proteins and receptor molecules have variousindustrial applications, including as pharmaceutical and diagnosticagents. Receptor immunoadhesins, for instance, can be employed astherapeutic agents to block receptor-ligand interaction. Themembrane-bound proteins can also be employed for screening of potentialpeptide or small molecule inhibitors of the relevant receptor/ligandinteraction. Efforts are being undertaken by both industry and academiato identify new, native receptor proteins. Many efforts are focused onthe screening of mammalian recombinant DNA libraries to identify thecoding sequences for novel receptor proteins.

[0006] We herein describe the identification and characterization ofnovel secreted and transmembrane polypeptides and novel nucleic acidsencoding those polypeptides.

[0007] 1. PRO213

[0008] Human growth arrest-specific gene 6 (gas6) encodes a protein thatis expressed in a variety of different tissues and which has beenreported to be highly expressed during periods of serum starvation andnegatively regulated during growth induction. See Manfioletti et al.,Mol. Cell. Biol. 13(8):4976-4985 (1993) and Stitt et al., Cell80:661-670 (1995). Manfioletti et al. (1993), supra, have suggested thatthe gas6 protein is member of the vitamin K-dependent family ofproteins, wherein the members of the latter family of proteins (whichinclude, for example, Protein S, Protein C and Factor X) all playregulatory roles in the blood coagulation pathway. Thus, it has beensuggested that gas6 may play a role in the regulation of a proteasecascade relevant in growth regulation or in the blood coagulationcascade.

[0009] Given the physiological importance of the gas6 protein, effortsare currently being undertaken by both industry and academia to identifynew, native proteins which are homologous to gas6. Many of these effortsare focused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel secreted and membrane-boundreceptor proteins, specifically those having homology to gas6. Examplesof such screening methods and techniques are described in the literature[see, for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113(1996); U.S. Pat. No. 5,536,637)]. We herein describe the identificationof a novel polypeptide which has homology to the gas6 polypeptide.

[0010] 2. PRO274

[0011] The 7-transmembrane (“7TM”) proteins or receptors, also referredto in the literature as G-protein coupled receptors, are specializedproteins designed for recognition of ligands and the subsequent signaltransduction of information contained within those ligands to themachinery of the cell. The primary purpose of cell surface receptors isto discriminate appropriate ligands from the various extracellularstimuli which each cell encounters, then to activate an effector systemthat produces an intracellular signal, thereby controlling cellularprocesses. [Dohlman, H.,Ann. Rev. Biochem., 60:653 (1991)]. The abilityof 7TM receptors to bind ligand to a recognition domain andallosterically transmit the information to an intracellular domain is aspecialized feature of 7TM proteins [Kenakin, T., Pharmacol. Rev.,48:413 (1996)]. The gene family which encodes the 7TM receptors orG-protein linked receptors encode receptors which recognize a largenumber of ligands, including but not limited to, C5a, interleukin 8 andrelated chemokines. Research in this area suggests that distinct signalsat the cell surface feed into common pathways of cell activation.[Gerard, C. and Gerard, N.,Curr. Op. Immunol., 6:140 (1994), Gerard, C.and Gerard, N.,Ann. Rev. Immunol., 12:775 (1994)]. The superfamily of7TM or G-protein coupled receptors contains several hundred members ableto recognize various messages such as photons, ions and amino acidsamong others [Schwartz, T. W., et al., H.,Trends in Pharmacol. Sci.,17(6):213 (1996)].

[0012] [Dohlman, H.,Ann. Rev. Biochem., 60:653 (1991)]. [Schwartz, T.W., et al., H.,Eur. J. Pharm. Sci., 2:85 (1994)]. We describe herein theidentification of a novel polypeptide (designated herein as PRO274)which has homology to the 7 transmembrane segment receptor proteins andthe Fn54 protein.

[0013] 3. PRO300

[0014] The Diff 33 protein is over-expressed in mouse testicular tumors.At present its role is unclear, however, it may play a role in cancer.Given the medical importance of understanding the physiology of cancer,efforts are currently being under taken to identify new, native proteinswhich are involved in cancer. We describe herein the identification of anovel polypeptide which has homology to Diff 33, designated herein asPRO300.

[0015] 4. PRO284

[0016] Efforts arre currently being undertaken to identify andcharacterize novel transmembrane proteins. We herein describe theidentification and characterization of a novel transmembranepolypeptide, designated herein as PRO284.

[0017] 5. PRO296

[0018] Cancerous cells often express numerous proteins that are notexpressed in the corresponding normal cell type or are expressed atdifferent levels than in the corresponding normal cell type. Many ofthese proteins are involved in inducing the transformation from a normalcell to a cancerous cell or in maintaining the cancer phenotype. Assuch, there is significant interest in identifying and characterizingproteins that are expressed in cancerous cells. We herein describe theidentification and characterization of a novel polypeptide havinghomology to the sarcoma-amplified protein SAS, designated herein asPRO296.

[0019] 6. PRO329

[0020] Immunoglobulin molecules play roles in many important mammalianphysiological processes. The structure of immunoglobulin molecules hasbeen extensively studied and it has been well documented that intactimmunoglobulins possess distinct domains, one of which is the constantdomain or F_(c) region of the immunoglobulin molecule. The F_(c) domainof an immunoglobulin, while not being directly involved in antigenrecognition and binding, does mediate the ability of the immunoglobulinmolecule, either uncomplexed or complexed with its respective antigen,to bind to F_(c) receptors either circulating in the serum or on thesurface of cells. The ability of an F_(c) domain of an immunoglobulin tobind to an F_(c) receptor molecule results in a variety of importantactivities, including for example, in mounting an immune responseagainst unwanted foreign particles. As such, there is substantialinterest in identifying novel F_(c) receptor proteins and subunitsthereof. We herein describe the identification and characterization of anovel polypeptide having homology to a high affinity immunoglobulinF_(c) receptor protein, designated herein as PRO329.

[0021] 7. PRO362

[0022] Colorectal carcinoma is a malignant neoplastic disease which hasa high incidence in the Western world, particularly in the UnitedStates. Tumors of this type often metastasize through lymphatic andvascular channels and result in the death of some 62,000 persons in theUnited States annually.

[0023] Monoclonal antibody A33 (mAbA33) is a murine immunoglobulin thathas undergone extensive preclinical analysis and localization studies inpatients inflicted with colorectal carcinoma (Welt et al., J. Clin.Oncol. 8:1894-1906 (1990) and Welt et al., J. Clin. Oncol. 12:1561-1571(1994)). mAbA33 has been shown to bind to an antigen found in and on thesurface of normal colon cells and colon cancer cells. In carcinomasoriginating from the colonic mucosa, the A33 antigen is expressedhomogeneously in more than 95% of the cases. The A33 antigen, however,has not been detecting in a wide range of other normal tissues, i.e.,its expression appears to be rather organ specific. Therefore, the A33antigen appears to play an important role in the induction of colorectalcancer.

[0024] Given the obvious importance of the A33 antigen in tumor cellformation and/or proliferation, there is substantial interest inidentifying homologs of the A33 antigen. In this regard, we hereindescribe the identification and characterization of a novel polypeptidehaving homology to the A33 antigen protein, designated herein as PRO362.

[0025] 8. PRO363

[0026] The cell surface protein HCAR is a membrane-bound protein thatacts as a receptor for subgroup C of the adenoviruses and subgroup B ofthe coxsackieviruses. Thus, RCAR may provide a means for mediating viralinfection of cells in that the presence of the HCAR receptor on thecellular surface provides a binding site for viral particles, therebyfacilitating viral infection.

[0027] In light of the physiological importance of membrane-boundproteins and spcficially those which serve a cell surface receptor forviruses, efforts are currently being undertaken by both industry andacademia to identify new, native membrane-bound reeptor proteins. Manyof these efforts are focused on the screening of mammalian recombinantDNA libraries to identify the coding sequences for novel receptorproteins. We herein describe a novel membrane-bound polypeptide havinghomology to the cell surface protein HCAR and to various tumor antigensincluding A33 and carcinoembryonic antigen, designated herein as PRO363,wherein this polypeptide may be a novel cell surface virus receptor ortumor antigen.

[0028] 9. PRO868

[0029] Control of cell numbers in mammals is believed to be determined,in part, by a balance between cell proliferation and cell death. Oneform of cell death, sometimes referred to as necrotic cell death, istypically characterized as a pathologic form of cell death resultingfrom some trauma or cellular injury. In contrast, there is another,“physiologic” form of cell death which usually proceeds in an orderly orcontrolled manner. This orderly or controlled form of cell death isoften referred to as “apoptosis” [see, e.g., Barr et al.,Bio/Technology, 12:487-493 (1994); Steller et al., Science,267:1445-1449 (1995)]. Apoptotic cell death naturally occurs in manyphysiological processes, including embryonic development and clonalselection in the immune system [Itoh et al., Cell 66:233-243 (1991)].Decreased levels of apoptotic cell death have been associated with avariety of pathological conditions, including cancer, lupus, and herpesvirus infection [Thompson, Science, 267:1456-1462 (1995)]. Increasedlevels of apoptotic cell death may be associated with a variety of otherpathological conditions, including AIDS, Alheimer's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, multiple sclerosis, retinitispigmentosa, cerebellar degeneration, aplastic anemia, myocardialinfarction, stroke, reperfusion injury, and toxin-induced liver disease[see, Thompson, supra].

[0030] Apoptotic cell death is typically accompanied by one or morecharacteristic morphological and biochemical changes in cells, such ascondensation of cytoplasm, loss of plasma membrare microvilli,segmentation of the nucleus, degradation of chromosomal DNA or loss ofmitochondrial function. A variety of extrinsic and intrinsic signals arebelieved to trigger or induce such morphological and biochemicalcellular changes [Raff, Nature, 356:397-400 (1992); Steller, supra;Sachs et al., Blood, 82:15 (1993)]. For instance, they can be triggeredby hormonal stimuli, such as glucocorticoid hormones for immaturethymocytes, as well as withdrawal of certain growth factors[Watanabe-Fukunaga et al., Nature, 356:314-317 (1992)]. Also, someidentified oncogenes such as myc, rel, and E1A, and tumor suppressors,like p53, have been reported to have a role in inducing apoptosis.Certain chemotherapy drugs and some forms of radiation have likewisebeen observed to have apoptosis-inducing activity [Thompson, supra].

[0031] Various molecules, such as tumor necrosis factor-α (“TNF-α”),tumor necrosis factor-β (“TNF-β” or “lymphotoxin-α”), lymphotoxin-β(“LT-β”), CD30 ligand, CD27 ligand, CD40 ligand, OX-40 ligand, 4-1BBligand, Apo-1 ligand (also referred to as Fas ligand or CD95 ligand),and Apo-2 ligand (also referred to as TRAIL) have been identified asmembers of the tumor necrosis factor (“TNF”) family of cytokines [See,e.g., Gruss and Dower, Blood, 85:3378-3404 (1995); Pitti et al., J.Biol. Chem., 271:12687-12690 (1996); Wiley et al., Immunity, 3:673-682(1995); Browning et al., Cell, 72:847-856 (1993); Armitage et al.Nature, 357:80-82 (1992), WO 97/01633 published Jan. 16, 1997; WO97/25428 published Jul. 17, 1997]. Among these molecules, TNF-α, TNF-β,CD30 ligand, 4-1BB ligand, Apo-1 ligand, and Apo-2 ligand (TRAIL) havebeen reported to be involved in apoptotic cell death. Both TNF-α andTNF-β have been reported to induce apoptotic death in susceptible tumorcells [Schmid et al., Proc. Natl. Acad. Sci., 83:1881 (1986); Dealtry etal., Eur. J. Immunol., 17:689 (1987)]. Zheng et al. have reported thatTNF-α is involved in post-stimulation apoptosis of CD8-positive T cells[Zheng et al., Nature, 377:348-351 (1995)]. Other investigators havereported that CD30 ligand may be involved in deletion of self-reactive Tcells in the thymus [Amakawa et al., Cold Spring Harbor LaboratorySymposium on Programmed Cell Death, Abstr. No. 10, (1995)].

[0032] Mutations in the mouse Fas/Apo-1 receptor or ligand genes (calledIpr and gld, respectively) have been associated with some autoimmunedisorders, indicating that Apo-1 ligand may play a role in regulatingthe clonal deletion of self-reactive lymphocytes in the periphery[Krammer et al., Curr. Op. Immunol., 6:279-289 (1994); Nagata et al.,Science, 267:1449-1456 (1995)]. Apo-1 ligand is also reported to inducepost-stimulation apoptosis in CD4-positive T lymphocytes and in Blymphocytes, and may be involved in the elimination of activatedlymphocytes when their function is no longer needed [Krammer et al.,supra; Nagata et al., supra]. Agonist mouse monoclonal antibodiesspecifically binding to the Apo-1 receptor have been reported to exhibitcell killing activity that is comparable to or similar to that of TNF-α[Yonehara et al., J. Exp. Med., 169:1747-1756 (1989)].

[0033] Induction of various cellular responses mediated by such TNFfamily cytokines is believed to be initiated by their binding tospecific cell receptors. Two distinct TNF receptors of approximately55-kDa (TNFR1) and 75-kDa (TNFR2) have been identified [Hohman et al.,J. Biol. Chem., 264:14927-14934 (1989); Brockhaus et al., Proc. Natl.Acad. Sci., 87:3127-3131 (1990); EP 417,563, published Mar. 20, 1991]and human and mouse cDNAs corresponding to both receptor types have beenisolated and characterized [Loetscher et al., Cell, 61:351 (1990);Schall et al., Cell, 61:361 (1990); Smith et al., Science 248:1019-1023(1990); Lewis et al., Proc. Natl. Acad. Sci., 88:2830-2834 (1991);Goodwin et al., Mol. Cell. Biol., 11:3020-3026 (1991)]. Extensivepolymorphisms have been associated with both TNF receptor genes [see,e.g., Takao et al., Immunogenetics, 37:199-203 (1993)]. Both TNFRs sharethe typical structure of cell surface receptors including extracellular,transmembrane and intracellular regions. The extracellular portions ofboth receptors are found naturally also as soluble TNF-binding proteins[Nophar, Y. et al., EMBO J., 9:3269 (1990); and Kohno, T. et al., Proc.Natl. Acad. Sci. U.S.A., 87:8331 (1990)]. More recently, the cloning ofrecombinant soluble TNF receptors was reported by Hale et al. [J. Cell.Biochem. Supplement 15F, 1991, p. 113 (P424)].

[0034] The extracellular portion of type 1 and type 2 TNFRs (TNFR1 andTNFR2) contains a repetitive amino acid sequence pattern of fourcysteine-rich domains (CRDs) designated 1 through 4, starting from theNH₂-terminus. Each CRD is about 40 amino acids long and contains 4 to 6cysteine residues at positions which are well conserved [Schall et al.,supra; Loetscher et al., supra; Smith et al., supra; Nophar et al.,.sura; Kohno et al., supra]. In TNFR1, the approximate boundaries of thefour CRDs are as follows: CRD1-amino acids 14 to about 53; CRD2- aminoacids from about 54 to about 97; CRD3- amino acids from about 98 toabout 138; CRD4- amino acids from about 139 to about 167. In TNFR2, CRD1includes amino acids 17 to about 54; CRD2- amino acids from about 55 toabout 97; CRD3- amino acids from about 98 to about 140; and CRD4- aminoacids from about 141 to about 179 [Banner et al., Cell, 73:431-435(1993)]. The potential role of the CRDs in ligand binding is alsodescribed by Banner et al., supra.

[0035] A similar repetitive pattern of CRDs exists in several othercell-surface proteins, including the p75 nerve growth factor receptor(NGFR) [Johnson et al., Cell, 47:545 (1986); Radeke et al., Nature,325:593 (1987)], the B cell antigen CD40 [Stamenkovic et al., EMBO J.,8:1403 (1989)], the T cell antigen OX40 [Mallet et al., EMBO J., 2:1063(1990)] and the Fas antigen [Yonehara et al., supra and Itoh et al.,Cell, 66:233-243 (1991)]. CRDs are also found in the soluble TNFR(sTNFR)-like T2 proteins of the Shope and myxoma poxviruses [Upton etal., Virology, 160:20-29 (1987); Smith et al., Biochem. Biophys. Res.Commun., 176:335 (1991); Upton et al., Virology, 184:370 (1991)].Optimal alignment of these sequences indicates that the positions of thecysteine residues are well conserved. These receptors are sometimescollectively referred to as members of the TNF/NGF receptor superfamily.Recent studies on p75NGFR showed that the deletion of CRD1 [Welcher, A.A. et al., Proc. Natl. Acad. Sci. USA, 88:159-163 (1991)] or a 5-aminoacid insertion in this domain [Yan, H. and Chao, M. V., J. Biol. Chem.,266:12099- 12104 (1991)] had little or no effect on NGF binding [Yan, H.and Chao, M. V., supra]. p75 NGFR contains a proline-rich stretch ofabout 60 amino acids, between its CRD4 and transmembrane region, whichis not involved in NGF binding [Peetre, C. et al., Eur. J. Hematol.,41:414-419(1988); Seckinger, P. et al., J. Biol. Chem., 264:11966-11973(1989); Yan, H. and Chao, M. V., supra]. A similar proline-rich regionis found in TNFR2 but not in TNFR1.

[0036] The TNF family ligands identified to date, with the exception oflymphotoxin-α, are type II transmembrane proteins, whose C-terminus isextracellular. In contrast, most receptors in the TNF receptor (TNFR)family identified to date are type I transmembrane proteins. In both theTNF ligand and receptor families, however, homology identified betweenfamily members has been found mainly in the extracellular domain(“ECD”). Several of the TNF family cytokines, including TNF-α, Apo-1ligand and CD40 ligand, are cleaved proteolytically at the cell surface;the resulting protein in each case typically forms a homotrimericmolecule that functions as a soluble cytokine. TNF receptor familyproteins are also usually cleaved proteolytically to release solublereceptor ECDs that can function as inhibitors of the cognate cytokines.

[0037] Recently, other members of the TNFR family have been identified.Such newly identified members of the TNFR family include CAR1, HVEM andosteoprotegerin (OPG) [Brojatsch et al., Cell, 87:845-855 (1996);Montgomery et al., Cell, 87:427-436 (1996); Marsters et al., J. Biol.Chem., 272:14029-14032 (1997); Simonet et al., Cell, 89:309-319 (1997)].Unlike other known TNFR-like molecules, Simonet et al., supra, reportthat OPG contains no hydrophobic transmembrane-spanning sequence.

[0038] Moreover, a new member of the TNF/NGF receptor family has beenidentified in mouse, a receptor referred to as “GITR” for“glucocorticoid-induced tumor necrosis factor receptor family-relatedgene” [Nocentini et al., Proc. Natl. Acad. Sci. USA 94:6216-6221(1997)]. The mouse GITR receptor is a 228 amino acid type Itransmembrane protein that is expressed in normal mouse T lymphocytesfrom thymus, spleen and lymph nodes. Expression of the mouse GITRreceptor was induced in T lymphocytes upon activation with anti-CD3antibodies, Con A or phorbol 12-myristate 13-acetate. It was speculatedby the authors that the mouse GITR receptor was involved in theregulation of T cell receptor-mediated cell death.

[0039] In Marsters et al., Curr. Biol., 6:750 (1995), investigatorsdescribe a full length native sequence human polypeptide, called Apo-3,which exhibits similarity to the TNFR family in its extracellularcysteine-rich repeats and resembles TNFR1 and CD95 in that it contains acytoplasmic death domain sequence [see also Marsters et al., Curr.Biol., 6:1669 (1996)]. Apo-3 has also been referred to by otherinvestigators as DR3, wsl-1 and TRAMP [Chinnaiyan et al., Science,274:990 (1996); Kitson et al., Nature, 384:372 (1996); Bodmer et al.,Immunity, 6:79 (1997)].

[0040] Pan et al. have disclosed another TNF receptor family memberreferred to as “DR4” [Pan et al., Science, 276:111-113 (1997)]. The DR4was reported to contain a cytoplasmic death domain capable of engagingthe cell suicide apparatus. Pan et al. disclose that DR4 is believed tobe a receptor for the ligand known as Apo-2 ligand or TRAIL.

[0041] In Sheridan et al., Science, 277:818-821 (1997) and Pan et al.,Science, 277:815-818 (1997), another molecule believed to be a receptorfor the Apo-2 ligand (TRAIL) is described. That molecule is referred toas DR5 (it has also been alternatively referred to as Apo-2). Like DR4,DR5 is reported to contain a cytoplasmic death domain and be capable ofsignaling apoptosis.

[0042] In Sheridan et al., supra, a receptor called DcR1 (oralternatively, Apo-2DcR) is disclosed as being a potential decoyreceptor for Apo-2 ligand (TRAIL). Sheridan et al. report that DcR1 caninhibit Apo-2 ligand function in vitro. See also, Pan et al., supra, fordisclosure on the decoy receptor referred to as TRID.

[0043] For a review of the TNF family of cytokines and their receptors,see Gruss and Dower, supra.

[0044] As presently understood, the cell death program contains at leastthree important elements—activators, inhibitors, and effectors; in C.elegans, these elements are encoded respectively by three genes, Ced-4,Ced-9 and Ced-3 [Steller, Science, 267:1445 (1995); Chinnaiyan et al.,Science, 275:1122-1126 (1997); Wang et al., Cell, 90:1-20 (1997)]. Twoof the ThFR family members, TNFR1 and Fas/Apol (CD95), can activateapoptotic cell death [Chinnaiyan and Dixit, Current Biology, 6:555-562(1996); Fraser and Evan, Cell; 85:781-784 (1996)]. TNFR1 is also knownto mediate activation of the transcription factor, NF-κB [Tartaglia etal., Cell, 74:845-853 (1993); Hsu et al., Cell, 84:299-308 (1996)]. Inaddition to some ECD homology, these two receptors share homology intheir intracellular domain (ICD) in an oligomerization interface knownas the death domain [Tartaglia et al., supra; Nagata, Cell, 88:355(1997)]. Death domains are also found in several metazoan proteins thatregulate apoptosis, namely, the Drosophila protein, Reaper, and themammalian proteins referred to as FADD/MORT1, TRADD, and RIP [Cleavelandand Ihle, Cell, 81:479-482 (1995)].

[0045] Upon ligand binding and receptor clustering, TNFR1 and CD95 arebelieved to recruit FADD into a death-inducing signalling complex. CD95purportedly binds FADD directly, while TNFR1 binds FADD indirectly viaTRADD [Chinnaiyan et al., Cell, 81:505-512 (1995); Boldin et al., J.Biol. Chem., 270:387-391 (1995); Hsu et al., supra; Chinnaiyan et al.,J. Biol. Chem., 271:4961-4965 (1996)]. It has been reported that FADDserves as an adaptor protein which recruits the Ced-3-related protease,MACHα/FLICE (caspase 8), into the death signalling complex [Boldin etal., Cell, 85:803-815 (1996); Muzio et al., Cell, 85:817-827 (1996)].MACHα/FLICE appears to be the trigger that sets off a cascade ofapoptotic proteases, including the interleukin-1β converting enzyme(ICE) and CPP32/Yama, which may execute some critical aspects of thecell death programme Fraser and Evan, supra].

[0046] It was recently disclosed that programmed cell death involves theactivity of members of a family of cysteine proteases related to the C.elegans cell death gene, ced-3, and to the mammalian IL-1-convertingenzyme, ICE. The activity of the ICE and CPP32/Yama proteases can beinhibited by the product of the cowpox virus gene, crmA [Ray et al.,Cell, 69:597-604 (1992); Tewari et al., Cell 81:801-809 (1995)]. Recentstudies show that CrmA can inhibit TNFR1- and CD95-induced cell death[Enari et al., Nature 375:78-81 (1995); Tewari et al., J. Biol. Chem.,270:3255-3260 (1995)].

[0047] As reviewed recently by Tewari et al., TNFR1, TNFR2 and CD40modulate the expression of proinflammatory and costimulatory cytokines,cytokine receptors, and cell adhesion molecules through activation ofthe transcription factor, NF-κB [Tewari et al., Curr. Op. Genet.Develop., 6:39-44 (1996)]. NF-κB is the prototype of a family of dimerictranscription factors whose subunits contain conserved Rel regions[Verma et al., Genes Develop., 9:2723-2735 (1996); Baldwin, Ann. Rev.Immunol., 14:649-681 (1996)]. In its latent form, NF-κB is complexedwith members of the IκB inhibitor family; upon inactivation of the IκBin response to certain stimuli, released NF-κB translocates to thenucleus where it binds to specific DNA sequences and activates genetranscription.

[0048] 10. PRO382

[0049] Proteases are enzymatic proteins which are involved in a largenumber of very important biological processes in mammalian andnon-mammalian organisms. Numerous different protease enzymes from avariety of different mammalian and non-mammalian organisms have beenboth identified and characterized, including the serine proteases whichexhibit specific activity toward various serine-containing proteins. Themammalian protease enzymes play important roles in biological processessuch as, for example, protein digestion, activation, inactivation, ormodulation of peptide hormone activity, and alteration of the physicalproperties of proteins and enzymes.

[0050] In light of the important physiological roles played by proteaseenzymes, efforts are currently being undertaken by both industry andacademia to identify new, native protease homologs. Many of theseefforts are focused on the screening of mammalian recombinant DNAlibraries to identify the coding sequences for novel membrane-boundreceptor proteins. Examples of screening methods and techniques aredescribed in the literature [see, for example, Klein et al., Proc. Natl.Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)]. We hereindescribe the identification of novel polypeptides having homology toserine protease enzymes, designated herein as PRO382 polypeptides.

[0051] 11. PRO545

[0052] The ADAM (A Disintegrin And Metalloprotease) family of proteinsof which meltrin is a member may have an important role in cellinteractions and in modulating cellular responses. [see, for example,Gilpin et al., J. Biol. Chem., 273(1):157-166 (1998)]. The ADAM proteinshave been implicated incarcinogenesis. Meltrin-α (ADAM12) is a myoblastgene product reported to be required for cell fusion. [Harris et al., J.Cell. Biochem., 67(1):136-142 (1997), Yagami-Hiromasa et al., Nature,377:652-656 (1995)]. The meltrins contain disintegrin andmetalloprotease domains and are implicated in cell adhesive eventsinvolved in development, through the integrin-binding disintegrindomain, but also have an anti-adhesive finction through a zinc-dependentmetalloprotease domain. [Alfandari et al., Devel. Biol., 182(2):314-330(1997)]. Given the medical importance of cell fusion and modulation ofcellular responses in carcinogenesis and other disease mechanisms,efforts are currently being under taken to identify new, native proteinswhich are involved in cell fusion and modulation of cellular responses.We describe herein the identification of a novel polypeptide which hashomology to meltrin, designated herein as PRO545.

[0053] 12. PRO617

[0054] CD24 is a protein that is associated with the cell surface of avariety of different cells of the mammalian immune system, including forexample, neutrophils, monocytes and some lymphocytes, for example, Blymphocytes. CD24 has been shown to be a ligand for theplatelet-associated surface glycoprotein P-selectin (also known asgranule membrane protein-140 or GMP-140), a glycoprotein that isconstitutively synthesized in both platelets and endothelial cells andbecomes exposed on the surface of platelets when those cells becomeactivated. In this way, P-selectin mediates the calcium-dependentadhesion of activated platelets and endothelial cells to the variouscells of the immune system that express one or more ligands for theP-selectin molecule, particularly CD24. This mechanism allows forrecruitment of immune system cells to locations where they are mostneeded, for example, sites of injury. Thus, there is substantialinterest in identifying novel polypeptides that exhibit homology to thecell surface antigens of the immune system cells. We herein describe theidentification and characterization of a novel polypeptide havinghomology to the CD24 protein, wherein that novel polypeptide is hereindesignated PRO617.

[0055] 13. PRO700

[0056] Protein-isulfide isomerase (PDI) is a catalyst of disulfideformation and isomerization diring protein folding. It has two catalyticsites housed in two domains homologous to thioredoxin, one near the Nterminus and the other near the C terminus. [See for example, Gilbert HF, J.Biol.Chem., 47:29399-29402 (1997), Mayfield K J, Science,278:1954-1957 (1997) and Puig et al., J.Biol.Chem., 52:32988-32994(1997)]. PDI is useful for formation of natural type disulfide bonds ina protein which is produced in aprokaryotic cell. (See also, U.S. Pat.Nos. 5,700,659 and 5,700,678).

[0057] Thus, PDI and molecules related thereto are of interest,particularly for ability to catalyze the formation of disulfide bonds.Moreover, these molecules are generally of interest in the study ofredox reactions and related processes. PDI and related molecules arefurther described in Darby, et al., Biochemistry 34, 11725-11735 (1995).We herein describe the identification and characterization of novelpolypeptides having homology to protein disulfide isomerase, designatedherein as PRO700 polypeptides.

[0058] 14. PRO702

[0059] Conglutinin is a bovine serum protein that was originallydescribed as a vertebrate lectin protein and which belongs to the familyof C-type lectins that have four characteristic domains, (1) anN-terminal cysteinerich domain, (2) a collagen-like domain, (3) a neckdomain and (4) a carbohydrate recognition domain (CRD). Recent reportshave demonstrated that bovine conglutinin can inhibit hemagglutinationby influenza A viruses as a result of their lectin properties (Eda etal., Biochem. J. 316:43-48 (1996)). It has also been suggested thatlectins such as conglutinin can function as immunoglobulin-independentdefense molecules due to complement-mediated mechanisms. Thus,conglutinin has been shown to be useful for purifying immune complexesin vitro and for removing circulating immune complexes from patientsplasma in vivo (Lim et al., Biochem. Biophys. Res. Commun. 218:260-266(1996)). We herein describe the identification and characterization of anovel polypeptide having homology to the conglutinin protein, designatedherein as PRO702.

[0060] 15. PRO703

[0061] Very-long-chain acyl-CoA synthetase (“VLCAS”) is a long-chainfatty acid transport protein which is active in the cellular transportof long and very long chain fatty acids. [see for example, Uchida etal., J. Biochem (Tokyo) 119(3):565-571 (1996) and Uchiyama et al., JBiol Chem 271(48):30360-30365 (1996). Given the biological importance offatty acid transport mechanisms, efforts are currently being under takento identify new, native proteins which are involved in fatty acidtransport. We describe herein the identification of a novel polypeptidewhich has homology to VLCAS, designated herein as PRO703.

[0062] 16. PRO705

[0063] The glypicans are a family of glycosylphosphatidylinositol(GPI)-anchored proteoglycans that, by virtue of their cell surfacelocalization and possession of heparin sulfate chains, may regulate theresponses of cells to numerous heparin-binding growth factors, celladhesion molecules and extracellular matrix components. Mutations in oneglypican protein cause of syndrome of human birth defects, suggestingthat the glypicans may play an important role in development (Litwack etal., Dev. Dyn. 211:72-87 (1998)). Also, since the glypicans may interactwith the various extracellular matrices, they may also play importantroles in wound healing (McGrath et al., Pathol. 183:251-252 (1997)).Furthermore, since glypicans are expressed in neurons and glioma cells,they may also play an important role in the regulation of cell divisionand survival of cells of the nervous system (Liang et al., J. Cell.Biol. 139:851-864 (1997)). It is evident, therefore, that the glypicansare an extremely important family of proteoglycans. There is, therefore,substantial interest in identifying novel polypeptides having homologyto members of the glypican family. We herein describe the identificationand characterization of a novel polypeptide having homology toK-glypican, designated herein as PRO705.

[0064] 17. PRO708

[0065] Aryl sulfatases are enzymes that exist in a number of differentisoforms, including aryl sulfatase A (ASA), aryl sulfatase B (ASB) andaryl sulfatase C (ASC), and that function to hydrolyze a variety ofdifferent aromatic sulfates. Aryl sulfatases have been isolated from avariety of different animal tissues and microbial sources and theirstructures and functions have been extensively studied (see, e.g.,Nichol and Roy, J. Biochem. 55:643-651 (1964)). ASA deficiency has beenreported to be associated with metachromatic leukodystrophy (MLD) (Gileset al., Prenat. Diagn. 7(4):245-252 (1987) and Herska et al., Am. J.Med. Genet. 26(3):629-635 (1987)). Additionally, other groups havereported that aryl sulfatases have been found in high levels in naturalkiller cells of the immune system and have hypothesized a possible rolefor these enzymes in NK cell-mediated cellular lysis (see, e.g.,Zucker-Franklin et al., Proc. Natl. Acad. Sci. USA 80(22):6977-6981(1983)). Given the obvious physiological importance of the arylsulfatase enzymes, there is a substantial interest in identifying novelaryl sulfatase homolog polypeptides. We herein describe theidentification and characterization of novel polypeptides havinghomology to the aryl sulfatases, wherein these novel polypeptides areherein designated PRO708 polypeptides.

[0066] 18. PRO320

[0067] Fibulin-1 is a cysteine-rich, calcium-binding extracellularmatrix (ECM) component of basement membranes and connective tissueelastic fibers and plasma protein, which has four isoforms, A-D, derivedfrom alternative splicing. Fibulin-1 is a modular glycoprotein withamino-terminal anaphlatoxin-like modules followed by nine epidermalgrowth factor (EGF)-like modules and, depending on alternative splicing,four possible carboxyl termini. Fibulin-2 is a novel extracellularmatrix protein frequently found in close association with microfibrilscontaining either fibronectin or fibrillin. There are multiple forms offibulin-1 that differ in their C-terminal regions that are producedthrough the process of alternative splicing of their precursor RNA. [seefor example Tran et al., Matrix Biol 15(7):479-493 (1997).]

[0068] Northern and Western blotting analysis of 16 cell linesestablished from tumors formed in athymic mice and malignant cell linesderived from patients indicate that low expression of fibulin-1D plays arole in tumor formation and invasion. [Qing et al., Oncogene,18:2159-2168 (1997)]. Ovarian-cancer cells are characterized by theirability to invade freely the peritoneal cavity. It has been demonstratedthat estradiol stimulates the proliferation of estrogen-receptor(ER)-positive ovarian-cancer cells, as well as expression of fibulin-1.Studies on the effect of fibulin-1 on motility of the MDA-MB231breast-cancer cell line, indicated inhibition of haptotactic migrationof MDA-MB231 cells, and the authors concluded that fibulin-1 can inhibitcancer cell motility in vitro and therefore has the potential to inhibittumor invasion. [Hayashido et al., Int. J Cancer, 75(4):654-658 (1998)]

[0069] Thus, fibulin, and molecules related thereto are of interest,particularly for the use of preventing cancer. Moreover, these moleculesare generally of interest in the study of connective tissue andattachment molecules and related mechanisms. Fibulin and relatedmolecules are further described in Adams, et al., J. Mol. Biol.,272(2):226-36 (1997); Kielty and Shuttleworth, Microsc. Res. Tech.,38(4):413-27 (1997); and Child. J. Card. Surg. 12(2Supp.):131-5 (1997).

[0070] We herein describe the identification and characterization ofnovel polypeptides having homology to fibulin, designated herein asPRO320 polypeptides.

[0071] 19. PRO324

[0072] Oxidoreductases are enzymes that catalyze a reaction in which twomolecules of a compound interact so that one molecule is oxidized andthe other is reduced, with a molecule of water entering the reaction.There are many different types of oxidoreductase enzymes that play veryimportant physiological roles in the mammalian organism. Some of themost important oxidoreductases include, for example, lyases, lactases,cholesterol oxidases, and the like. These enzymes play roles in suchessential processes as digestion, signal transduction, maintenance ofionic homeostasis, and the like. As such, given that oxidoreductaseenzymes find various essential uses in the mammalian organism, there isa substantial interest in identifying novel oxidoreductase enzymehomologs. We herein describe the identification and characterization ofa novel polypeptide having homology to oxidoreductases, designatedherein as PRO324.

[0073] 20. PRO351

[0074] Prostasin is a novel human serine proteinase purified from humanseminal fluid. Immunohistochemical localization reveals that prostasinis present in epithelial cells and ducts of the prostate gland. The cDNAfor prostasin has been cloned and characterized. Southern blot analysis,following a reverse transcription polymerase chain reaction, indicatesthat prostasin mRNA is expressed in prostate, liver, salivary gland,kidney, lung, pancreas, colon, bronchus, renal proximal tubular cells,and prostate carcinoma LNCaP cells. Cellular localization of prostasinmRNA was identified within epithelial cells of the human prostate glandby in situ hybridization histochemistry. [See for example, Yu et al., JBiol Chem. (1994) 269(29):18843-18848, and Yu et al., J Biol Chem.(1994) 270(22):13483-13489].

[0075] Thus, prostasin, and molecules related thereto are of interest,particularly for the study, diagnosis and treatment of medicalconditions involving the prostate. Prostasin and related molecules arefurther described in Yu et al., Genomics (1996) 32(3):334-340. We hereindescribe the identification and characterization of novel polypeptideshaving homology to prostasin, designated herein as PRO351 polypeptides.

[0076] 21. PRO352

[0077] Butyrophilin is a milk glycoprotein that constitutes more than40% of the total protein associated with the fat globule membrane inmanmalian milk. Expression of butyrophilin mRNA has been shown tocorrelate with the onset of milk fat production toward the end pregnancyand is maintained throughout lactation. Butyrophilin has been identifiedin bovine, murine and human (see Taylor et al., Biochim. Biophys. Acta1306:1-4 (1996), Ishii et al., Biochim. Biophys. Acta 1245:285-292(1995), Mather et al., J. Dairy Sci. 76:3832-3850 (1993) and Banghart etal., J. Biol. Chem. 273:4171-4179 (1998)) and is a type I transmembraneprotein that is incorporated into the fat globulin membrane. It has beensuggested that butyrophilin may play a role as the principle scaffoldfor the assembly of a complex with xanthine dehydrogenase/oxidase andother proteins that function in the budding and release of milk-fatglobules from the apical surface during lactation (Banghart et al.,supra).

[0078] Given that butyrophilin plays an obviously important role inmammalian milk production, there is substantial interest in identifyingnovel butyrophilin homologs. We herein describe the identification andcharacterization of a novel polypeptide having homology to butyrophilin,designated herein as PRO352.

[0079] 22. PRO381

[0080] The immunophilins are a family of proteins that function asreceptors for immunosuppressant drugs, such as cyclosporin A, FK506, andrapamycin. The immunophilins occur in two separate classes, (1) theFK506-binding proteins (FKBPs), which bind to FK506 and rapamycin, and(2) the cyclophilins, which bind to cyclosporin A. With regard to theFK506-binding proteins, it has been reported that the FK506/FKBP complexfunctions to inhibit the activity of the serine/threonine proteinphosphatase 2B (calcineurin), thereby providing immunosuppressantactivity (Gold, Mol. Neurobiol. 15:285-306 (1997)). It has also beenreported that the FKBP immunophilins are found in the mammalian nervoussystem and may be involved in axonal regeneration in the central nervoussystem through a mechanism that is independent of the process by whichimmunosuppression is achieved (Gold, supra). Thus, there is substantialinterest in identifying novel polypeptides having homology to the FKBPimmunophilins. We herein describe the identification andcharacterization of a novel polypeptide having homology to an FKBPimmunophilin protein, designated herein as PRO381.

[0081] 23. PRO386

[0082] Mammalian cell membranes perform very important functionsrelating to the structural integrity and activity of various cells andtissues. Of particular interest in membrane physiology is the study oftransmembrane ion channels which act to directly control a varietyofphysiological, pharmacological and cellular processes. Numerous ionchannels have been identified including calcium (Ca), sodium (Na) andpotassium (K) channels, each of which have been analyzed in detail todetermine their roles in physiological processes in vertebrate andinsect cells.

[0083] One type of cell membrane-associated ion channel, the sodiumchannel, plays an extremely important role in a cell's ability tomaintain ionic homeostasis as well as transmit intracellular andextracellular signals. Voltage-gated sodium channels in brain neuronshave been shown to be complexes of a pore-forming alpha unit withsmaller beta-1 and beta-2 subunits (Isom et al., Cell 83:433-442(1995)). Given the obvious importance of sodium channels in cellularhomeostasis and other important physiological functions, there is asignificant interest in identifying novel polypeptides having homologyto sodium channel subunits. We herein describe the identification andcharacterization of a novel polypeptide having homology to the beta-2subunit of the rat sodium channel, designated herein as PRO386.

[0084] 24. PRO540

[0085] Lecithn-cholesterol acyltransferase (“LCAT”), also known asphosphatidylcholine-sterol acyltransferase is a key enzyme in theintravascular metabolism of high density lipoproteins, specifically inthe process of cholesterol metabolism. [see, for example, Brousseau etal., J. Lipid Res., 38(12):2537-2547 (1997), Hill et al., Biochem. J.,294:879-884 (1993), and Drayna et al., Nature 327 (6123):632-634(1987)]. Given the medical importance of lipid metabolism, efforts arecurrently being under taken to identify new, native proteins which areinvolved in lipid transport. We describe herein the identification of anovel polypeptide which has homology to LCAT, designated herein asPRO540.

[0086] 25. PRO615

[0087] Synaptogyrin is a synaptic vesicle protein that is uniformlydistributed in the nervous system. The cDNA encoding synaptogyrin hasbeen cloned and sequenced and the sequence predicts a protein with amolecular mass of 25,900 D with four membrane-spanning domains.Synaptogyrin has been implicated in membrane traffic to and from theplasma membrane. Stenius et al., J. Cell. Biol. 131(6-2):1801-1809(1995). In addition, a novel isoform of synaptogyrin called cellugyrinexhibits sequence identity with synaptogyrin. In rat tissues, cellugyrinand synaptogyrins are expressed in mirror image patterns. Cellugyrin isubiquitously present in all tissues tested with the lowest levels inbrain tissue, whereas synaptogyrin protein is only detectable in brain.In rat tissues, cellugyrin and synaptogyrins are expressed in mirrorimage patterns. The synaptic vesicle protein synaptogyrin may be aspecialized version of a ubiquitous protein, cellugyrin, with the twoproteins sharing structural similarity but differing in localization.This finding supports the emerging concept of synaptic vesicles as thesimplified and specialized form of a generic trafficking organelle.[Janz et al., J. Biol. Chem. 273(5):2851-2857 (1998)] . The sequence forcellugyrin derived from the Norway rat, Rattus norvegicus has beendeposited in the Genbank database on Dec. 23, 1997, designated accessionnumber AF039085. See also, Janz et al., J. Biol. Chem. 273 (1998), inpress.

[0088] Given the medical importance of synaptic transmission, effortsare currently being under taken to identify new, native proteins thatmay be part of a simplified and specialized generic traffickingorganelle in the form of synaptic vesicles. We describe herein theidentification of a novel polypeptide which has homology tosynaptogyrin, designated herein as PRO615.

[0089] 26. PRO618

[0090] Enteropeptidase is a key enzyme in the intestinal digestioncascade specifically cleaves the acidic propeptide from trypsinogen toyield active trypsin. This cleavage initiates a cascade of proteolyticreactions leading to the activation of many pancreatic zymogens.

[0091] See, for example, Matsushima et al., J. Biol. Chem. 269(31):19976-19982 (1994), Kitamoto et al., Proc. Nat. Acad. Sci.,91(16):7588-7592 (1994). Enterokinase (enteropeptidase) is a related tomammain serine proteases involved in digestion, coagulation, andfibrinolysis. LaVallie et al., J Biol Chem., 268(31):23311-23317 (1993).

[0092] Given the medical importance of digestive processes, efforts arecurrently being under taken to identify new, native proteins that may beinvolved in digestion, coagulation, and fibrinolysis. We describe hereinthe identification of a novel polypeptide which has homology toenteropeptidase, designated herein as PRO618.

[0093] 27. PRO719

[0094] Lipoprotein lipase is a key enzyme that mediates the hydrolysisof triglycerides and phospholipids present in circulating plasmalipoproteins (Dugi et al., J. Biol. Chem.. 270:25396-25401 (1995)).Moreover, lipoprotein lipase has been shown to mediate the uptake oflipoproteins into cells, wherein cellular uptake of lipoproteins isinitiated by binding of lipoprotein lipase to cell surface proteoglycansand to tile low density lipoprotein (LDL) receptor-related protein(Krapp et al., J. Lipid Res. 36:2362-2373 (1995)). Thus, it is clearthat lipoprotein lipase plays an extremely important role in lipoproteinand cholesterol metabolism. There is, therefore, substantial interest inidentifying novel polypeptides that share sequence homology and/orbiological activity with lipoprotein lipase. We herein describe theidentification and characterization of a novel polypeptide havingsequence homology to lipoprotein lipase H, designated heein as PRO719.

[0095] 28. PRO724

[0096] The low density lipoprotein (LDL) receptor is a membrane-boundprotein that plays a key role in cholesterol homeostasis, mediatingcellular uptake of lipoprotein particles by high affinity binding to itsligands, apolipoprotein (apo) B-100 and apoE. The ligand-binding domainof the LDL receptor contains 7 cysteine-rich repeats of approximately 40amino acids, wherein each repeat contains 6 cysteines, which form 3intra-repeat disulfide bonds. These unique structural features providetile LDL receptor with its ability to specifically interact with apoB-100 and apoE, thereby allowing for transport of theselipoproteinparticles across cellular membranes and metabolism of theircomponents. Soluble fragments containing the extracellular domain of theIDL receptor have been shown to retain the ability to interact with itsspecific lipoprotein ligands (Simmons et al., J. Biol. Chem.272:25531-25536 (1997)). Thus, it is clear that the LDL receptor isintimately involved in important physiological activities related tocholesterol metabolism. As such, there is substantial interest inidentifying novel LDL receptor homolog proteins. We herein describe theidentification and characterization of a novel polypeptide havinghomology to the human LDL receptor protein, designated herein as PRO724.

[0097] 29. PRO772

[0098] Expression of the human gene A4 is enriched in the colonicepithelium and is transcriptionally activated on differentiation ofcolonic epithelial cells in vitro (Oliva et al., Arch. Biochem. Biophys.302:183-192 (1993) and Oliva et al., Am. J. Physiol. 272:C957-C965(1997)). A4 cDNA contains an open reading frame that predicts apolypeptide of approximately 17 kilodaltons in size. Hydropathy analysisof the A4 protein revealed four putative membrane-spanningalpha-helices. Immunocytochemical studies of cells expressing A4 proteinindicated that expression is localized to the endoplasmic reticulum. Thefour membrane-spanning domains and the biophysical characteristics ofthe A4 protein suggest that it belongs to a family of integral membraneproteins called proteolipids, some of which multimerize to form ionchannels. In fact, preliminary evidence has suggested that A4 may itselfmultinerize and take on the properties of an ion channel (Oliva et al.,Am. J. Physiol. 272:C957-C965 (1997)). Given the importance of ionchannels in maintaining cellular homeostasis, there is a significantinterest in identifying novel polypeptides having homology to known andputative ion channels. We herein describe the identification andcharacterization of a novel polypeptide having homology to the putativeion channel protein, A4, designated herein as PRO772.

[0099] 30. PRO852

[0100] Proteases are enzymatic proteins which are involved in a largenumber of very important biological processes in mammalian andnon-mammalian organisms. Numerous different protease enzymes from avariety of different mammalian and non-mammalian organisms have beenboth identified and characterized. The mammalian protease enzymes playimportant roles inmany different biological processes including, forexample, protein digestion, activation, inactivation, or modulation ofpeptide hormone activity, and alteration of the physical properties ofproteins and enzymes.

[0101] In light of the important physiological roles played by proteaseenzymes, efforts are currently being undertaken by both industry andacademia to identifr new, native protease homologs. Many of theseefforts are focused on the screening of mammalian recombinant DNAlibraries to identify the coding sequences for novel secreted andmembrane-bound receptor proteins. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)]. We herein descnbe the identification of novel polypeptideshaving homology to various protease enzymes, designated herein as PRO852polypeptides.

[0102] 31. PRO853

[0103] Studies have reported that the redox state of the cell is animportant determinant of the fate of the cell. Furthermore, reactiveoxygen species have been reported to be cytotoxic, causing inflammatorydisease, including tissue necrosis, organ failure, atherosclerosis,infertility, birth defects, premature aging, mutations and malignancy.Thus, the control of oxidation and reduction is important for a numberof reasons, including the control and prevention of strokes, heartattacks, oxidative stress, hypertension and may be associated with thedevelopment of malignancies. The levels of antioxidant enzymes, such asreductases, which catalyze the conversion of reactive oxygen species towater have been shown to be low in cancer cells. In particular,malignant prostate epithelium may have lowered expression of suchantioxidant enzymes [Baker et ., Prostate 32(4):229-233 (1997)]. In thisregard, reductases, are of interest. In addition, the transcriptionfactors, NF-kappa B and AP-1, are known to be regulated by redox stateand to affect the expression of a large variety of genes thought to beinvolved in the pathogenesis of AIDS, cancer, atherosclerosis anddiabetic complications. Publications further describing this subjectmatter include Engman et al., Anticancer Res. (Greece), 17:4599-4605(1997), Kelsey, et al., Br. J. Cancer, 76(7):8524 (1997); Friedrich andWeiss, J. Theor. Biol., 187 (4):52940 (1997) and Pieulle, et al., J.Bacteriol., 179(18):5684-92 (1997). Given the physiological importanceof redox reactions in vivo, efforts are currently being under taken toidentify new, native proteins which are involved in redox reactions. Wedescribe herein the identification of a novel prostate specificpolypeptide which has sequence similarity to reductase, designatedherein as PRO853.

[0104] 32. PRO860

[0105] Neurofascin is a member of the L1 subgroup of the cellularadhesion molecule (“CAM”) family of nervous system adhesion moleculesand is involved in cellular aggregation. Cell-cell recognition andpatterning of cell contacts have a critical role in mediating reversibleassembly of a wide variety or transcellular complexes in the nervoussystem. Cell interactions may be regulated through modulation of ankyrinbinding to neurofascin. See, for example, Tuvia et al., Proc. Nat Acad.Sci., 94(24) 12957-12962 (1997). Neurofascin has been described as amember of the L1 subgroup of the immunoglobulin superfamily implicatedin neurite extension during embryonic development for which numerousisoforms have been detected at various stages of development. See alsoHassel et al., J. Biol. Chem., 272(45) 28742-28749 (1997), Grumet.,Cell. Tissue Res. 290(2) 423-428 (1997), Garver et al., J. Cell. Biol.,137:703-714 (1997), and Lambert et al., J. Neurosci., 17:7025-7-36(1997),.

[0106] Given the physiological importance of cellular adhesion moleculesand development of the nervous system in vivo, efforts are currentlybeing under taken to identify new, native proteins which are involved inregulation of cellular interactions in the nervous system. We describeherein the identification and characterization of a novel polypeptidewhich has sequence similarity to neurofascin, designated herein asPRO860.

[0107] 33. PRO846

[0108] The CMRF35 monoclonal antibody was used to identify a cellmembrane antigen, designated CMRF35, which is present on the surface ofmonocytes, neutrophils, a proportion of peripheral blood T and Blymphocytes and lymphocytic cell lines. The CMRF35 cDNA encodes a novelintegral membrane glycoprotein member of the immunoglobulin (Ig) genesuperfamily. The molecule comprises (a) a single extracellular Igvariable domain remarkably similar to the Fc receptor for polymeric IgAand IgM, (b) a membrane-proximal domain containing a high proportion ofproline, serine and threonine residues that was predicted to be heavilyO-glycosylated, (c) an unusual transmembrane anchor that contained aglutamic acid and a proline residue and (d) a short cytoplasmic tail.Transcripts encoding the CMRF35 protein have been detected in earlymonocytic cell lines, in peripheral blood T cells and in some Blymphoblastoid cell lines, confirming the results of immulocytologicalstaining. Jackson et al., Eur. J. Immunol. 22(5):1157-1163 (1992).CMRF-35 molecules are differentially expressed in hematopoietic cells,and the expression of the antigen was shown to be markedly influenced bystimulation with mitogens and cytokines. See, for example, Clark et al.,Exp. Hematol. 25(8):759 (1997), Daish et al., Immunol. 79(1):55-63(1993), and Clark et al., Tissue Antigens 48:461 (1996).

[0109] Given the physiological importance of the immune system andantigens associated with various immune system cells, efforts arecurrently being under taken to identify new, native proteins which areexpressed on various cells of the immune system. We describe herein theidentification of a novel polypeptide which has sequence similarity toCMRF35, designated herein as PRO846.

[0110] 34. PRO862

[0111] Lysozyme is a protein which is widely distributed in severalhuman tissues and secretions including milk, tears and saliva. It hasbeen demonstrated to hydrolyze linkages between N-acetylglucosamines. Ithas been demonstrated to be an inhibitor of chemotaxis and of theproduction of toxic oxygen free radicals and may also have some role inthe calcification process. As such, there is substantial interest inidentifying novel polypeptides having homology to lysozyme. We describeherein the identification of a novel polypeptide which has sequencesimilarity to lysozyme.

[0112] 35. PRO864

[0113] Wnt-4 is a secreted glycoprotein which correlates with, and isrequired for, kidney tubulogenesis. Mice lacking Wnt-4 activity fail toform pretubular cell aggregates; however, other aspects of mesenchymaland ureteric development are unaffected. Thus, Wnt-4 appears to act asan autoinducer of the mesenchyme to epithelial transition that underliesnephron development. Stark et al., Nature ;372(6507):679-683 (1994). Inaddition, members of the Wnt gene family code for cysteine-rich,secreted proteins, which are differentially expressed in the developingbrain and possibly act as intercellular signaling molecules. A Wnt gene,e.g., Wnt-1 is known to be essential for specification of the midbraincell fate. Yoshioka et al., Biochem. Bioiphys. Res. Commun.203(3):1581-1588 (1994). Several member of the Wnt family of secretedfactors are strongly implicated as regulators of mammary cellular growthand differentiation. Shimizu et al., Cell Growth Differ. 8(12)1349-1358. Wnt-4 is normally expressed in early pregnancy. Wnt-4 maytherefore be a local signal driving epithelial branching in pregnancy.Edwards P A, Biochem Soc Svmp.63:21-34 (1998). See also, Lipschutz J H,Am. J. Kidney Dis. 31(3):383-397, (1998). We describe herein theidentification and characterizaton of a novel polypeptide which hassequence similarity to Wnt-4, designated herein as PRO864.

[0114] 36. PRO792

[0115] At least two cell-derived signals have been shown to be necessaryfor the induction of immunoglobulin isotype switching in B-cells. Thefirst signal is given by either of the soluble lymphokines, interleukin(IL)-4 or IL-13, which induce germline epsilon transcript expression,but this alone is insufficient to trigger secretion of immunoglobulin E(IgE). The second signal is provided by a physical interaction betweenB-cells and activated T-cells, basophils and mast cells, and it has beenshown that the CD40/CD40 ligand pairing is crucial for mediating IgEsynthesis. Additionally, amongst the numerous pairs of surface adhesionmolecules that are involved in IgE synthesis, the CD23/CD21 pair appearsto play a key role in the generation of IgE. CD23 is a protein that ispositively and negatively regulated by factors which increase ordecrease IgE, production, respectively. Antibodies to CD23 have beenshown to inhibit IL-4-induced human IgE production in vitro and toinhibit antigen-specific IgE responses in a rat model, in an isotypeselective manner (Bonnefoy et al., Eur. Respir. J. Suppl. 22:63S-66S(1996)). CD23 interacts with CD21 on B-cells, preferentially driving IgEproduction. Given that the CD23 protein plays an extremely importantrole in the induction of a mammalian IgE response, there is significantinterest in identifying novel polypeptides having homology to CD23. Weherein describe the identification and characterization of a novelpolypeptide having homology to CD23, designated herein as PRO792.

[0116] 37. PRO866

[0117] Mindin and spondin proteins are secreted proteins that arestructurally related to one another and which have been identified in avariety of organisms. For example, Higashijima et al., Dev Biol.192:211-227 (1997) have reported the identification of spondin andmindin expression in floor plate cells in the zebrafish embryonic axis,thereby suggesting that mindin and spondin prtoteins play importantroles in embryonic development. This same group has reported that mindinand spondin proteins finction as extracellular matrix proteins that havea high affinity for the basal lamina. (Id.). It has been reported thatF-spondin is a secreted protein that promotes neural adhesion andneurite extension (Klar et al., Cell 69:95-110 (1992) and that M-spondinis an extracellular matrix protein that localizes to muscle attachmentsites in Drosophila (Umemiya et al., Dev. Biol. 186:165-176 (1997)).Thus, there is significant inteest in identifying novel polypeptideshaving homology to the mindin and spondin proteins. We herein describethe identification and characterization of a novel polypeptide havinghomology to mindin2 and mindin1, designated herein as PRO866.

[0118] 38. PRO871

[0119] Cyclophilins are a family of proteins that bind to cyclosporin Aand possess peptidyl-prolyl cis-trans isomerase activity (Sherry et al.,Proc. Natl. Acad. Sci. USA 95:1758-1763 (1998)). In addition,cyclophilins are secreted by activated cells and act in a cytokine-likemanner, presumably via signaling through a cell surface cyclophilinreceptor. Host cell-derived cyclophilin A has been shown to beincorporated into HIV-1 virions and its incorporation has been shown tobe essential for viral infectivity. Thus, one or more the cyclophins maybe directly associated with HIV-1 infectivity. Given the obviousimportance of the cyclophilin proteins, there is substantial interest inidentifying novel polypeptides which have sequence homology to one ormore of the cyclophilin proteins. We herein describe the identificationand characterization of a novel polypeptide having homology tocyclophilin-like protein CyP-60, designated herein as PRO871.

[0120] 39. PRO873

[0121] Enzymatic proteins play important roles in the chemical reactionsinvolved in the digestion of foods, the biosynthesis of macromolecules,the controlled release and utilization of chemical energy, and otherprocesses necessary to sustain life. Enzymes have also been shown toplay important roles in combating various diseases and disorders. Forexample, liver carboxylesterases have been reported to assist insensitizing human tumor cells to the cancer prodrugs. Danks et al.,report that stable expression of the cDNA encoding a carboxylesterase inRh30 human rhabdomyosarcoma cells increased the sensitivity of the cellsto the CPT-11 cancer prodrug 8.1-fold. Cancer Res. (1998) 58(1):20-22.The authors propose that this prodrug/enzyme combination could beexploited therapeutically in a manner analogous to approaches currentlyunder investigation with the combinations of ganciclovir/herpes simplexvirus thymidine kinase and 5-fluorocytosine/cytosine deaminase. van Peltet al. demonstrated that a 55 kD human liver carboxylesterase inhibitsthe invasion of Plasmodium falciparum malaria sporozoites into primaryhuman hepatocytes in culture. J Hepatol (1997) 27(4):688-698.

[0122] Carboxylesterases have also been found to be of importance in thedetoxification of drugs, pesticides and other xenobiotics. Purifiedhuman liver carboxylesterases have been shown to be involved in themetabolism of various drugs including cocaine and heroin. Prindel et aLdescribe the purification and cloning of a broad substrate specificityhuman liver carboxylesterase which catalyzes the hydrolysis of cocaineand heroin and which may play an important role in the degradation ofthese drugs in human tissues. J. Biol. Chem. (1997)6:272(23):14769-14775. Brzenzinski et al. describe a spectrophotometriccompetitive inhibition assay used to identify drug or environmentalesters that are metabolized by carboxylesterases. Drug Metab Dispos(1997) 25(9):1089-1096.

[0123] In light of the important physiological roles played bycarboxylesterases, efforts are being undertaken by both industry andacademia to identify new, native carboxylesterase homologs. We hereindescribe the identification and characterization of anovel polypeptidehaving homology to carboxylesterase, designated herein as PRO873.

[0124] 40. PRO940

[0125] CD33 is a cell-surface protein that is a member of thesialoadhesin family of proteins that are capable of mediatingsialic-acid dependent binding with distinct specificities for both thetype of sialic acid and its linkage to subterminal sugars. CD33 isspecifically expressed in early myeloid and some monocyte cell lineagesand has been shown to be strongly associated with various myeloid tumorsincluding, for example, acute nonlymphocytic leukemia (ANLL). As such,CD33 has been suggested as a potential target for the treatment ofcancers associated with high level expression of the protein. There is,therefore, significant interest in the identification of novelpolypeptides having homology to CD33. In fact, one CD33 homolog(designated CD33L) has already been identified and described (see Takeiet al., Cytogenet. Cell Genet. 78:295-300 (1997)). We herein describethe identification of another novel polypeptide having homology to CD33,designated herein as PRO940. The novel polypeptide described herein alsoexhibits significant homology to the human OB binding proteinsdesignated HSU71382_(—)1 and HSU71383_(—)1 in the Dayhoff database(version 35.45 SwissProt 35).

[0126] 41. PRO941

[0127] Cadherins are a large family of transmembrane proteins. Cadherinscomprise a family of calcium-dependent glycoproteins that function inmediating cell-cell adhesion in virtually all solid tissues ofmulticellular organisms. At least cadherins 1-13 as well as types B, E,EP, M, N, P and R have been identified and characterized. Among thefunctions cadherins are known for, with some exceptions, are thatcadherins participate in cell aggregation and are associated withcell-cell adhesion sites. Recently, it has been reported that while allcadherins share multiple repeats of a cadherin specific motif believedto correspond to folding of extracellular domains, members of thecadherin superfamily have divergent structures and, possibly, functions.In particular it has been reported that members of the cadherinsuperfamily are involved in signal transduction. See, Suzuki, J. CellBiochem., 61(4):531-542 (1996). Cadherins are further described inTanihara etal., J. Cell Sci., 107(6):1697-1704 (1994), Aberle et al., J.Cell Biochem., 61(4):514-523 (1996) and Tanihara et al., Cell Adhes.Commun., 2(1):15-26 (1994). We herein describe the identification andcharacterization of a novel polypeptide having homology to a cadherinprotein, designated herein as PRO941.

[0128] 42. PRO944

[0129]Clostridium perfringens enterotoxin (CPE) is considered to be thevirulence factor responsible for causing the symptoms of C. perfringenstype A food poisoning and may also be involved in other human andveterinary illnesses (McClane, Toxicon. 34:1335-1343 (1996)). CPEcarries out its adverse cellular functions by binding to anapproximately 50 kD cell surface receptor protein designated theClostridium perfringens enterotoxin receptor (CPE-R) to form anapproximately 90,000 kD complex on the surface of the cell. cDNAsencoding the CPE-R protein have been identified characterized in bothhuman and mouse (Kataira et al., J. Cell Biol. 136:1239-1247 (1997) andKatahira et al., J. Biol. Chem. 272:26652-26658 (1997)). Since the CPEtoxin has been reported to cause a variety of illnesses in mammalianhosts and those illnesses are initiated by binding of the CPE toxin tothe CPE-R, there is significant interest in identifying novel CPE-Rhomologs. We herein describe the identification and characterization ofa novel polypeptide having homology to the CPE-R, designated herein asPRO944.

[0130] 43. PRO983

[0131] Membrane-bound proteins include not only cell-surfacemembrane-bound proteins, but also proteins that are found on the surfaceof intracellular vesicles. These vesicles are involved in exocytosis,which is the fusion of secretory vesicles with the cellular plasmamembrane, and have two main functions. One is the discharge of thevesicle contents into the extracellular space, and the second is theincorporation of new proteins and lipids into the plasma membraneitself. Exocytosis can be either constitutive or regulated. Alleukaryotic cells exhibit constitutive exocytosis, which is marked by theimmediate fusion of the secretory vesicle after formation. In contrast,regulated exocytosis results in the accumulation of the secretoryvesicles that fuse with the plasma membrane upon receipt of anappropriate signal by vesicle-associated membrane proteins. Usually,this signal is an increase in the cytosolic free Ca²⁺ concentration.However, regulated exocytosis that is independent of Ca²⁺ has beenreported (see, e.g. Fujita-Yoshigaki et al. J. Biol. Chem. (1996)31:271(22):13130-13134). Regulated exocytosis is crucial to manyspecialized cells, including neurons (neurotransmitter release fromsynaptic vesicles), adrenal chromaffin cells (adrenaline secretion),pancreatic acinar cells (digestive enzyme secretion), pancreatic β-cells(insulin secretion), mast cells (histamine secretion), mammary cells(milk protein secretion), sperm (enzyme secretion), egg cells (creationof fertilization envelope) and adipocytes (insertion of glucosetransporters into the plasma membrane).

[0132] Disorders involving exocytosis are known. For example,inflammatory mediator release from mast cells leads to a variety ofdisorders, including asthma. Similarly, Chediak-Higashi Syndrome (CHS)is a rare autosomal recessive disease in which neutrophils, monocytesand lymphocytes contain giant cytoplasmic granules. Accordingly, theproteins involved in exocytosis are of paramount interest and effortsare being undertaken by both industry and academia to identify new,vesicle-associated proteins. For example, Skehel et al. identified a33-kilodalton membrane protein in Aplysia, termed VAP-33, which isrequired for the exocytosis of neurotransmitter. Science (1995)15:269(5230):1580-1583, and Neuropharmacology (1995) 34(11):1379-1385.Many efforts are focused on the screening of mammalian recombinant DNAlibraries to identify the coding sequences for novel vesicle- associatedmembrane proteins. It is an object of the invention to provide proteinshaving homology to the vesicle associated protein, VAP-33, designatedherein as PRO983.

[0133] 44. PRO1057

[0134] Proteases are enzymatic proteins which are involved in a largenumber of very important biological processes in mammalian andnon-mammalian organisms. Numerous different protease enzymes from avariety of different mammalian and non-mammalian organisms have beenboth identified and characterized. The mammalian protease enzymes playimportant roles in many different biological processes including, forexample, protein digestion, activation, inactivation, or modulation ofpeptide hormone activity, and alteration of the physical properties ofproteins and enzymes.

[0135] In light of the important physiological roles played by proteaseenzymes, efforts are currently being undertaken by both industry andacademia to identify new, native protease homologs. Many of theseefforts are focused on the screening of mammalian recombinant DNAlibraries to identify the coding sequences for novel secreted proteins.Examples of screening methods and techniques are described in theliterature [see, for example, Klein et al., Proc. Natl. Acad. Sci.,93:7108-7113 (1996); U.S. Pat. No. 5,536,637)]. We herein describe theidentification of novel polypeptides having homology to various proteaseenzymes, designated herein as PRO1057 polypeptides.

[0136] 45. PRO1071

[0137] Thrombospondin-1 is a trimeric high molecular weight glycoproteinthat is released from platelet alpha-granules in response to thrombinstimulation and that is also a transient component of the extracellularmatrix in developing and repairing tissues (Adams, Int. J. Biochem. CellBiol. 29:861-865 (1997) and Qian et al., Proc. Soc. Exp. Biol. Med.212:199-207 (1996)). A variety of factors regulate thrombospondinexpression and the protem is degraded by both extracellular andintracellular routes. Thrombospondin-1 functions as a cell adhesionmolecule and also modulates cell movement, cell proliferation, neuriteoutgrowth and angiogenesis. As such, there is substantial interest inidentifying novel polypeptides having homology to thrombospondin. Weherein describe the identification and characterization of a novelpolypeptide having homology to thrombospondin, designated herein asPRO1071.

[0138] 46. PRO1072

[0139] Studies have reported that the redox state of the cell is animportant determinant of the fate of the cell. Furthermore, reactiveoxygen species have been reported to be cytotoxic, causing inflammatorydisease, including tissue necrosis, organ failure, atherosclerosis,infertility, birth defects, premature aging, mutations and malignancy.Thus, the control of oxidation and reduction is important for a numberof reasons, including the control and prevention of strokes, heartattacks, oxidative stress, hypertension and may be associated with thedevelopment of malignancies. The levels of antioxidant enzymes, such asreductases, which catalyze the conversion of reactive oxygen species towater have been shown to be low in cancer cells. In particular,malignant prostate epithelium may have lowered expression of suchantioxidant enzymes [Baker et al., Prostate 32(4):229-233 (1997)]. Inthis regard, reductases, are of interest. In addition, the transcriptionfactors, NF-kappa B and AP-1, are known to be regulated by redox stateand to affect the expression of a large variety of genes thought to beinvolved in the pathogenesis of AIDS, cancer, atherosclerosis anddiabetic complications. Publications further describing this subjectmatter include Engman et al., Anticancer Res. (Greece), 17:4599-4605(1997), Kelsey, et al., Br. J. Cancer, 76(7):852-854 (1997); Friedrichand Weiss, J. Theor. Biol., 187(4):529-40 (1997) and Pieulle, et al., J.Bacteriol., 179(18):5684-92 (1997). Given the physiological importanceof redox reactions in vivo, efforts are currently being under taken toidentify new, native proteins which are involved in redox reactions. Wedescribe herein the identification of a novel polypeptide which hassequence similarity to reductase enzymes, desiignated herein as PRO1072.

[0140] 47. PRO1075

[0141] Protein disulfide isomerase is an enzymatic protein which isinvolved in the promotion of correct refolding of proteins through theestablishment of correct disulfide bond formation. Protein disulfideisomerase was initially identified based upon its ability to catalyzethe renaturation of reduced denatured RNAse (Goldberger et al., J. Biol.Chem. 239:1406-1410 (1964) and Epstein et al., Cold Sprring Harbor Symp.Quant. Biol. 28:439-449 (1963)). Protein disulfide isomerase has beenshown to be a resident enzyme of the endoplasmic reticulum which isretained in the endoplasmic reticulum via a -KDEL or -HDEL amino acidsequence at its C-terminus.

[0142] Given the importance of disulfide bond-forming enzymes and theirpotential uses in a number of different applications, for example inincreasing the yield of correct refolding of recombinantly producedproteins, efforts are currently being undertaken by both industry andacademia to identify new, native proteins having homology to proteindisulfide isomerase. Many of these efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the coding sequencesfor novel protein disulfide isomerase homologs. Examples of screeningmethods and techniques are described in the literature [see, forexample, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S.Pat. No. 5,536,637)]. We herein describe a novel polypeptide havinghomology to protein disulfide isomerase, designated herein as PRO1075.

[0143] 48. PRO181

[0144] In Drosophila, the dorsal-ventral polarity of the egg chamberdepends on the localization of the oocyte nucleus and the gurken RNA tothe dorsal-anterior corner of the oocyte. Gurken protein presumably actsas a ligand for the drosophila EGF receptor (torpedo/DER) expressed inthe somatic follicle cells surrounding the oocyte. Cornichon is a generequired in the germline for dorsal-ventral signaling (Roth et al., Cell81:967-978 (1995)). Comichon, gurken and torpedo also finction in anearlier signaling event that establishes posterior follicle cell fatesand specifies the anterior-posterior polarity of the egg chamber.Mutations in any or all of these genes prevent the formation of acorrectly polarized microtubule cytoskeleton required for properlocalization of the anterior and posterior determinants bicoid and oskarand for the asymmetric positioning of the oocyte nucleus. Thus, it isclear that the cornichon gene product plays an important role in earlydevelopment. We herein describe the identification and characterizationof a novel polypeptide having homology to the cornichon protein,designated herein as PRO181.

[0145] 49. PRO195

[0146] Efforts arre currently being undertaken to identify andcharacterize novel transmembrane proteins. We herein describe theidentification and characterization of a novel transmembranepolypeptide, designated herein as PRO195.

[0147] 50. PRO865

[0148] Efforts arre currently being undertaken to identify andcharacterize novel secreted proteins. We herein describe theidentification and characterization of a novel secreted polypeptide,designated herein as PRO865.

[0149] 51. PRO827

[0150] VLA-2 is an cell-surface integrin protein that has beenidentified and characterized in a number of mammalian organisms,including both mouse and human. VLA-2 has been shown to be a receptor onthe surface of cells for echovirus-1 (EV-1) which mediates infection ofVLA-2-expressing cells by EV-1 (Zhang et al., Virology 235(2):293-301(1997) and Bergelson et al., Science 255:1718-1720 (1992)). VLA-2 hasalso been shown to mediate the interaction of collagen with endotheliumduring in vitro vascular tube formation (Jackson et al., Cell Biol. Int.18(9):859-867 (1994)). Various other integrinproteins that share variousdegrees of amino acid sequence homology with VLA-2 have been identifiedand characterized in a variety of mammalian organism. These integrinshave been reported to play important roles in a variety of differentphysiological functions. Therefore, there is significant interest inidentifying novel polypeptides having homology to one or more of theintegrin proteins. We herein describe the identification andcharacterization of a novel polypeptide having homology to VLA-2integrin protein, designated herein as PRO827.

[0151] 52. PRO1114

[0152] Many important cytokine proteins have been identified andcharacterized and shown to signal through specific cell surface receptorcomplexes. For example, the class II cytokine receptor family (CRF2)includes the interferon receptors, the interleukin-10 receptor and thetissue factor CRFB4 (Spencer et al., J. Exp. Med. 187:571-578 (1998) andKotenko et al., EMBO J. 16:5894-5903 (1997)). Thus, the multitude ofbiological activities exhibited by the various cytokine proteins isabsolutely dependent upon the presence of cytokine receptor proteins onthe surface of target cells. There is, therefore, a significant interestin identifying and characterizing novel polypeptides having homology toone or more of the cytokine receptor family. We herein describe theidentification and characterization of a novel polypeptide havinghomology to cytokine receptor family-4 proteins, designated herein asPRO1117.

[0153] Interferons (IFNs) encompass a large family of secreted proteinsoccurring in vertebrates. Although they were originally named for theirantiviral activity, growing evidence supports a critical role for IFNsin cell growth and differentiation (Jaramillo et al., CancerInvestigation 13(3):327-338 (1995)). IFNs belong to a class of negativegrowth factors having the ability to inhibit the growth of a widevariety of cells with both normal and transformed phenotypes. IFNtherapy has been shown to be beneficial in the treatment of humanmalignancies such as Karposi's sarcoma, chronic myelogenous leukemia,non-Hodgkin's lymphoma, and hairy cell leukemia as well as in thetreatment of infectious diseases such as hepatitis B (Gamliel et al.,Scanning Microscopy 2(1):485-492 (1988), Einhorn et al., Med. Oncol. &Tumor Pharmacother. 10:25-29 (1993), Ringenberg et al., MissouriMedicine 85(1):21-26 (1988), Saracco et al., Journal of Gastroenterologyand Hepatology 10:668-673 (1995), Gonzalez-Mateos et al.,Hepato-Gastroenterology 42:893-899 (1995) and Malaguarnera et al.,Pharmacotherapy 17(5):998-1005 (1997)).

[0154] Interferons can be classified into two major groups based upontheir primary sequence. Type I interferons, IFN-α and IFN-β, are encodedby a superfamily of intronless genes consisting of the IFN-α gene familyand a single IFN-β gene that are thought to have arisen from a commonancestral gene. Type I interferons may be produced by most cell types.Type II IFN, or IFN-γ, is restricted to lymphocytes (T cells and naturalkiller cells) and is stimulated by nonspecific T cell activators orspecific antigens in vivo.

[0155] Although both type I and type II IFNs produce similar antiviraland antiproliferative effects, they act on distinct cell surfacereceptors, wherein the binding is generally species specific (Langer etal., Immunol. Today 9:393-400 (1988)). Both IFN-α and IFN-β bindcompetitively to the same high affinity type I receptor, whereas IFN-γbinds to a distinct type II receptor. The presence and number of IFNreceptors on the surface of a cell does not generally reflect thesensitivity of the cell to IFN, although it is clear that the effects ofthe IFN protein is mediated through binding to a cell surface interferonreceptor. As such, the identification and characterization of novelinterferon receptor proteins is of extreme interest.

[0156] We herein describe the identification and characterization ofnovel interferon receptor polypeptides, designated herein as “PRO1114interferon receptor” polypeptides. Thus, the PRO1114 polypeptides of thepresent invention represents a novel cell surface interferon receptor.

[0157] 53. PRO237

[0158] Carbonic anhydrase is an enzymatic protein that which aids carbondioxide transport and release in the mammalian blood system bycatalyzing the synthesis (and the dehydration) of carbonic acid from(and to) carbon dioxide and water. Thus, the actions of carbonicanhydrase are essential for a variety of important physiologicalreactions in the mammal. As such, there is significant interest in theidentification and characterization of novel polypeptides havinghomology to carbonic anhydrase. We herein describe the identificationand characterization of a novel polypeptide having homology to carbonicanhydrase, designated herein as PRO237.

[0159] 54. PRO541

[0160] Numerous trypsin inhibitory proteins have been identified andcharacterized (see, e.g., Yamakawa et al., Biochim. Biophys. Acta1395:202-208 (1998) and Mizuki et al., Mammalian Genome 3:274-280(1992)). Trypsin inhibitor proteins play important roles in a variety ofdifferent physiological and biological pathways and are specificallyinvolved in such processes as the regulation of protein degradation,digestion, and the like. Given the important roles played by suchenzymatic proteins, there is significant interest in identifying andcharacterizing novel polypeptides having homology to known trypsininhibitor proteins. We herein describe the identification andcharacterization of a novel polypeptide having homology to a trypsininhibitor protein, designated herein as PRO541.

[0161] 55. PRO273

[0162] Leukocytes include monocytes, macrophages, basophils, andeosinophils and play an important role in the immune response. Thesecells are important in the mechanisms initiated by T and/or Blymphocytes and secrete a range of cytokines which recruit and activateother inflammatory cells and contribute to tissue destruction.

[0163] Thus, investigation of the regulatory processes by whichleukocytes move to their appropriate destination and interact with othercells is critical. Currently, leukocytes are thought to move from theblood to injured or inflamed tissues by rolling along the endothelialcells of the blood vessel wall. This movement is mediated by transientinteractions between selectins and their ligands. Next, the leukocytemust move through the vessel wall and into the tissues. This diapedesisand extravasation step involves cell activation which promotes a morestable leukocyte-endothelial cell interaction, again mediated byintegrins and their ligands.

[0164] Chemokines are a large family of structurally related polypeptidecytokines. These molecules stimulate leukocyte movement and may explainleukocyte trafficking in different inflammatory situations. Chemokinesmediate the expression of particular adhesion molecules on endothelialcells, and they produce chemoattractants which activate specific celltypes. In addition, the chemokines stimulate proliferation and regulateactivation of specific cell types. In both of these activities,chemokines demonstrate a high degree of target cell specificity.

[0165] The chemokine family is divided into two subfamilies based onwhether two amino termnal cysteine residues are immediately adjacent(C-C) or separated by one amino acid (C-X-C). Chemokines of the C-X-Cfamily generally activate neutrophils and fibroblasts while the C-Cchemokines act on a more diverse group of target cells includingmonocytes/macrophages, basophils, eosinophils and T lymphocytes. Theknown chemokines of both subfamilies are synthesized by many diversecell types as reviewed in Thomson A. (1994) The Cytokine Handbook, 2 dEd. Academic Press, N.Y. Chemokines are also reviewed in Schall T J(1994) Chemotactic Cytokines: Targets for Therapeutic Development.International Business Communications, Southborough Mass. pp 180-270;and in Paul W E (1993) Fundamental Immunology, 3rd Ed. Raven Press, N.Y.pp 822-826.

[0166] Known chemokines of the C-X-C subfamily include macrophageinflammatory proteins alpha and beta (MIP-1 and MIP-2), interleukin-8(IL-8), and growth regulated protein (GRO-alpha and beta).

[0167] MIP-2 was first identified as a 6 kDa heparin binding proteinsecreted by the mouse macrophage cell line RAW 264.7 upon stimulationwith lipopolysaccharide (LPS). MIP-2 is a member of the C-X-C (or CXC)subfamily of chemokines. Mouse MIP-2 is chemotactic for humanneutrophils and induces local neutrophil infiltration when injected intothe foot pads of mice. Rat MIP-2 shows 86% amino acid homology to themouse MIP-2 and is chemotactic for rat neutrophils but does notstimulate migration of rat alveolar macrophages or human peripheralblood eosinophils or lymphocytes. In addition, the rat MIP-2 has beenshown to stimulate proliferation of rat alveolar epithelial cells butnot fibroblasts.

[0168] Current techniques for diagnosis of abnormalities in inflamed ordiseased issues mainly rely on observation of clinical symptoms orserological analyses of body tissues or fluids for hormones,polypeptides or various metabolites. Problems exist with thesediagnostic techniques. First, patients may not manifest clinicalsymptoms at early stages of disease. Second, serological tests do notalways differentiate between invasive diseases and genetic syndromes.Thus, the identification of expressed chemokines is important to thedevelopment of new diagnostic techniques, effective therapies, and toaid in the understanding of molecular pathogenesis.

[0169] To date, chemokines have been implicated in at least thefollowing conditions: psoriasis, inflammatory bowel disease, renaldisease, arthritis, immune-mediated alopecia, stroke, encephalitis, MS,hepatitis, and others. In addition, non-ELR-containing chemokines havebeen implicated in the inhibition of angiogenesis, thus indicating thatthese chemokines have a rule in tumor vascularization and tumorigenesis.

[0170] Therefore it is the object of this invention to identifypolypeptides and nucleic acids encoding the same which have sequenceidentity and similarity with cytokine-induced neutrophilchemoattractants, MIP-1, MIP-2, and other related proteins. The effortsof this object are provided herein.

[0171] 56. PRO701

[0172] Beta neurexins and neuroligins are plasma membrane proteins thatare displayed on the neuronal cell surface. Neuroligin 1 is enriched insynaptic plasma membranes and acts as a splice site-specific ligand forbeta neurexins as described in Ichtchenko, et al., Cell, 81(3):435-443(1995). The extracellular sequence of neuroligin 1 is composed of acatalytically inactive esterase domain homologous toacetylcliolinesterase. Neuroligin 2 and 3 are similar in structure andsequence to neuroligin 1. All neuroligins contain an N-terminalhydrophobic sequence with the characteristics of a cleaved signalpeptide followed by a large esterase homology domain, a highly conservedsingle transmembrane region, and a short cytoplasmic domain. The threeneuroligins are alternatively spliced at the same position and areexpressed at high levels only in the brain. Tight binding of the threeneuroligins to beta neurexins is observed only for beta neurexinslacking an insert in splice site 4. Thus, neuroligins constitute amultigene family of brain-specific proteins with distinct isoforms thatmay have overlapping functions in mediating recognition processesbetween neurons, see Ichtchenko, et al., J. Biol. Chem.,271(5):2676-2682 (1996). Moreover, neurexins and neuroligins have beenreported as functioning as adhesion molecules in a Ca²⁺ dependentreaction that is regulated by alternative splicing of beta neurexins,i.e., see Nguyen and Sudhof, J. Biol. Chem., 272(41):26032-26039 (1997).Given the foregoing, membrane bound proteins are of interest. Moregenerally, membrane-bound proteins and receptors can play an importantrole in the formation, differentiation and maintenance of multicellularorganisms. The fate of many individual cells, e.g., proliferation,migration, differentiation, or interaction with other cells, istypically governed by information received from other cells and/or theimmediate environment. This information is often transmitted by secretedpolypeptides (for instance, mitogenic factors, survival factors,cytotoxic factors, differentiation factors, neuropeptides, and hormones)which are, in turn, received and interpreted by diverse cell receptorsor membrane-bound proteins. Such membrane-bound proteins and cellreceptors include, but are not limited to, cytokine receptors, receptorkinases, receptor phosphatases, receptors involved in cell-cellinteractions, and cellular adhesin molecules like selectins andintegrins. For instance, transduction of signals that regulate cellgrowth and differentiation is regulated in part by phosphorylation ofvarious cellular proteins. Protein tyrosine kinases, enzymes thatcatalyze that process, can also act as growth factor receptors. Examplesinclude fibroblast growth factor receptor and nerve growth factorreceptor.

[0173] Membrane-bound proteins and receptor molecules have variousindustrial applications, including as pharmaceutical and diagnosticagents. Receptor immunoadhesins, for instance, can be employed astherapeutic agents to block receptor-ligand interaction. Themembrane-bound proteins can also be employed for screening of potentialpeptide or small molecule inhibitors of the relevant receptor/ligandinteraction.

[0174] Efforts are being undertaken by both industry and academia toidentify new, native membrane-bound receptor proteins, particularlythose having sequence identity andlor similarity with neuroligins 1, 2and 3. Many efforts are focused on the screening of mammalianrecombinant DNA libraries to identify the coding sequences for novelsecreted and membrane-bound receptor proteins. Examples of screeningmethods and techniques are described in the literature [see, forexample, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S.Pat. No. 5,536,637)]. The results of such efforts are provided herein.

[0175] 57. PRO704

[0176] VIP36 is localized to the Golgi apparatus and the cell surface,and belongs to a family of legume lectin homologues in the animalsecretory pathway that might be involved in the trafficking ofglycoproteins, glycolipids, or both. It is further believed that VIP36binds to sugar residues of glycosphingolipids and/orgycosylphosphatidyl-inositol anchors and might provide a link betweenthe extracellular/luminal face of glycolipid rafts and the cytoplasmicprotein segregation machinery. Further regarding VIP36, it is believedthat there is a signal at its C-terminus that matches an internalizationconsensus sequence which confers its ability to cycle between the plasmamembrane and Golgi. See, Fiedler, et al, EMBO J., 13(7):1729-1740(1994); Fiedler and Simons, J. Cell Sci., 109(1):271-276 (1996); Itin,et al., MBO J., 14(10):2250-2256 (1995). It is believed that VIP36 iseither the same as or very closely related to the human GP36b protein.VIP36 and/or GP36b are of interest.

[0177] More generally, vesicular, cytoplasmic, extracellular andmembrane-bound proteins play important roles in the formation,differentiation and maintenance of multicellular organisms. The fate ofmany individual cells, e.g., proliferation, migration, differentiation,or interaction with other cells, is typically governed by informationreceived from other cells and/or the immediate environment. Thisinformation is often transmitted by secreted polypeptides (for instance,mitogenic factors, survival factors, cytotoxic factors, differentiationfactors, neuropeptides, and hormones) which are, in turn, received andinterpreted by diverse cell receptors or membrane-bound proteins. Thesesecreted polypeptides or signaling molecules normally pass through thecellular secretory pathway to reach their site of action in theextracellular environment, usually at a membrane-bound receptor protein.

[0178] Secreted proteins have various industrial applications, includinguse as pharmaceuticals, diagnostics, biosensors and bioreactors. Infact, most protein drugs available at present, such as thrombolyticagents, interferons, interleukins, erythropoietins, colony stimulatingfactors, and various other cytokines, are secretory proteins. Theirreceptors, which are membrane-bound proteins, also have potential astherapeutic or diagnostic agents. Receptor immunoadhesins, for instance,can be employed as therapeutic agents to block receptor-ligandinteraction. Membrane-bound proteins can also be employed for screeningof potential peptide or small molecule inhibitors of the relevantreceptor/ligand interaction. Such membrane-bound proteins and cellreceptors include, but are not limited to, cytokine receptors, receptorkinases, receptor phosphatases, receptors involved in cell-cellinteractions, and cellular adhesin molecules like selectins andintegrins. Transduction of signals that regulate cell growth anddifferentiation is regulated in part by phosphorylation of variouscellular proteins. Protein tyrosine kinases, enzymes that catalyze thatprocess, can also act as growth factor receptors. Examples includefibroblast growth factor receptor and nerve growth factor receptor.

[0179] Efforts are being undertaken by both industry and academia toidentify new, native vesicular, cytoplasmic, secreted and membrane-boundreceptor proteins, particularly those having sequence identity and/orsimilarity with VIP36. Many efforts are focused on the screening ofmammalian recombinant DNA libraries to identify the coding sequences fornovel secreted and membrane-bound receptor proteins. Examples ofscreening methods and techniques are described in the literature [see,for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996);U.S. Pat. No. 5,536,637)].

[0180] 58. PRO706

[0181] Acid phophatase proteins are secreted proteins whichdephophorylate terminal phosphate groups under acidic pH conditions.Acid phophatases contain a RHGXRXP amino acid sequence, which ispredicted to be mechanistically significant. Acid phosphatases may haveimportant functions in the diagnosis and treatment of human diseases.For example, prostatic acid phosphatase is a secreted protein uniquelyexpressed in prostatic tissue and prostate cancer. The level ofprostatic acid phosphatase is a potential prognostic factor for localand biochemical control in prostate cancer patients treated withradiotherapy, as described in Lankford et al., Int. J. Radiat. Oncol.Biol. Phys. 38(2): 327-333 (1997). Research suggests that a cellularimmune response to prostatic acid phosphatase may mediate destructiveautoimmune prostatitis, and that xenogeneic forms of prostatic acidphosphatase may prove useful for immunotherapy of prostate cancer. SeeFong et al., J. Immunol. 169(7): 3113-3117(1997). Seminal prostatic acidphosphatase levels correlate significantly with very low sperm levels(oligospermia) in individuals over 35, see Singh et al., Singapore Med.J. 37(6): 598-599 (1996). Thus, prostatic acid phosphatase has beenimplicated in a variety of human diseases, and may have an importantfunction in diagnosis and therapy of these diseases. A series ofaminobenzylphosphatic acid compounds are highly potent inhibitors ofprostatic acid phosphatase, as described in Beers et al., Bioorg. Med.Chem. 4(10): 1693-1701 (1996).

[0182] More generally, extracellular proteins play an important role inthe formation, differentiation and maintenance of multicellularorganisms. The fate of many individual cells, e.g., proliferation,migration, differentiation, or interaction with other cells, istypically governed by information received from other cells and/or theimmediate environment. This information is often transmitted by secretedpolypeptides (for instance, mitogenic factors, survival factors,cytotoxic factors, differentiation factors, neuropeptides, and hormones)which are, in turn, received and interpreted by diverse cell receptorsor membrane-bound proteins. These secreted polypeptides or signalingmolecules normally pass through the cellular secretory pathway to reachtheir site of action in the extracellular environment.

[0183] Secreted proteins have various industrial applications, includingpharmaceuticals, diagnostics, biosensors and bioreactors. Most proteindrugs available at present, such as thrombolytic agents, interferons,interleukins, erythropoietins, colony stimulating factors, and variousother cytokines, are secretory proteins. Their receptors, which aremembrane proteins, also have potential as therapeutic or diagnosticagents. Efforts are being undertaken by both industry and academia toidentify new, native secreted proteins, particularly those havingsequence identity with prostate acid phosphatase precursor and lysosomalacid phosphatase precursor and in some cases, those having identity withDNA found in fetal heart. Many efforts are focused on the screening ofmammalian recombinant DNA libraries to identify the coding sequences fornovel secreted proteins. Examples of screening methods and techniquesare described in the literature [see, for example, Klein et al., Proc.Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

[0184] 59. PRO707

[0185] Cadherins are a large family of transmembrane proteins. At leastcadherins 1-13 as well as types B, E, EP, M, N, P and R have beencharacterized. Among the functions cadherins are known for, with someexceptions, cadherins participate in cell aggregation and are associatedwith cell-cell adhesion sites. Cadherins are further described inTanihara, et al., J. Cell Sci., 107(6):1697-1704(1994) and Tanihara, etal., Cell Adhes. Commun., 2(1):15-26 (1994). Moreover, it has beenreported that some members of the cadherin superfamily are involved ingeneral cell-cell interaction processes including transduction. See,Suzuki, J. Cell Biochem., 61(4):531-542 (1996). Therefore, novel membersof the cadherin superfamily are of interest.

[0186] More generally, all novel proteins are of interest, includingmembrane-bound proteins. Membrane-bound proteins and receptors can playan important role in the formation, differentiation and maintenance ofmulticellular organisms. The fate of many individual cells, e.g.,proliferation, migration, differentiation, or interaction with othercells, is typically governed by information received from other cellsand/or the immediate environment. This information is often transmittedby secreted polypeptides (for instance, mitogenic factors, survivalfactors, cytotoxic factors, differentiation factors, neuropeptides, andhormones) which are, in turn, received and interpreted by diverse cellreceptors or membrane-bound proteins. Such membrane-bound proteins andcell receptors include, but are not limited to, cytokine receptors,receptor kinases, receptor phosphatases, receptors involved in cell-cellinteractions, and cellular adhesin molecules like selectins andintegrins. For instance, transduction of signals that regulate cellgrowth and differentiation is regulated in part by phosphorylation ofvarious cellular proteins. Protein tyrosine kinases, enzymes thatcatalyze that process, can also act as growth factor receptors. Examplesinclude fibroblast growth factor receptor and nerve growth factorreceptor.

[0187] Membrane-bound proteins and receptor molecules have variousindustrial applications, including as pharmaceutical and diagnosticagents. Receptor immunoadhesins, for instance, can be employed astherapeutic agents to block receptor-ligand interaction. Themembrane-bound proteins can also be employed for screening of potentialpeptide or small molecule inhibitors of the relevant receptor/ligandinteraction.

[0188] Efforts are being undertaken by both industry and academia toidentify new, native secreted and membrane-bound receptor proteins,particularly membrane bound proteins having identity with cadherins. Theresults of such efforts are provided herein.

[0189] 60. PRO322

[0190] Proteases are enzymatic proteins which are involved in a largenumber of very important biological processes in mammalian andnon-mammalian organisms. Numerous different protease enzymes from avariety of different mammalian and non-mammalian organisms have beenboth identified and characterized, including the serine proteases whichexhibit specific activity toward various serine-containing proteins. Themammalian protease enzymes play important roles in biological processessuch as, for example, protein digestion, activation, inactivation, ormodulation of peptide hormone activity, and alteration of the physicalproperties of proteins and enzymes.

[0191] Neuropsin is a novel serine protease whose mRNA is expressed inthe central nervous system. Mouse neuropsin has been cloned, and studieshave shown that it is involved in the hippocampal plasticity. Neuropsinhas also been indicated as associated with extracellular matrixmodifications and cell migrations. See, generally, Chen, et al.,Neurosci., 7(2):5088-5097 (1995) and Chen, et al., J. Histochem.Cytochem., 46:313-320 (1998).

[0192] Efforts are being undertaken by both industry and academia toidentify new, native membrane-bound or secreted proteins, particularlythose having homology to neuropsin, serine protease, neurosin andtrypsinogen. Many efforts are focused on the screening of mammalianrecombinant DNA libraries to identity the coding sequences for novelsecreted and membrane-bound receptor proteins. Examples of screeningmethods and techniques are described in the literature [see, forexample, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S.Pat. No. 5,536,637)].

[0193] 61. PRO526

[0194] Protein-protein interactions include those involved with receptorand antigen complexes and signaling mechanisms. As more is known aboutthe structural and functional mechanisms underlying protein-proteininteractions, protein-protein interactions can be more easilymanipulated to regulate the particular result of the protein-proteininteraction. Thus, the underlying mechanisms of protein-proteininteractions are of interest to the scientific and medical community.

[0195] All proteins containing leucine-rich repeats are thought to beinvolved in protein-protein interactions. Leucine-rich repeats are shortsequence motifs present in a number of proteins with diverse functionsand cellular locations. The crystal structure of ribonuclease inhibitorprotein has revealed that leucine-rich repeats correspond to beta-alphastructural units. These units are arranged so that they form a parallelbeta-sheet with one surface exposed to solvent, so that the proteinacquires an unusual, nonglobular shape. These two features have beenindicated as responsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415-421 (October 1994).

[0196] A study has been reported on leucine-rich proteoglycans whichserve as tissue organizers, orienting and ordering collagen fibrilsduring ontogeny and are involved in pathological processes such as woundhealing, tissue repair, and tumor stroma formation. lozzo, R. V., Crit.Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studiesimplicating leucine rich proteins in wound healing and tissue repair areDe La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany),37(4):215-222 (1995), reporting mutations in the leucine rich motif in acomplex associated with the bleeding disorder Bernard-Soulier syndrome,Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1): 111-116 (July1995), reporting that platelets have leucine rich repeats and Ruoslahti,E. I., et al., WO9110727-A by La Jolla Cancer Research Foundationreporting that decorin binding to transforming growth factorβ hasinvolvement in a treatment for cancer, wound healing and scarring.Related by function to this group of proteins is the insulin like growthfactor (IGF), in that it is useful in wound-healing and associatedtherapies concerned with re-growth of tissue, such as connective tissue,skin and bone; in promoting body growth in humans and animals; and instimulating other growth-related processes. The acid labile subunit(ALS) of IGF is also of interest in that it increases the half-life ofIGF and is part of the IGF complex in vivo. ALS is further described inLeong and Baxter, Mol. Endocrinol., 6(6):870-876 (1992); Baxter, J.Biol. Chem., 264(20):11843-11848 (1989); and Khosravi, et al., J. Clin.Endocrinol. Metab., 82(12):3944-3951 (1997).

[0197] Another protein which has been reported to have leucine-richrepeats is the SLIT protein which has been reported to be useful intreating neuro-degenerative diseases such as Alzheimer's disease, nervedamage such as in Parkinson's disease, and for diagnosis of cancer, see,Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1 by YaleUniversity. Also of interest is LIG-1, a membrane glycoprotein that isexpressed specifically in glial cells in the mouse brain, and hasleucine rich repeats and immunoglobulin-like domains. Suzuki, et al., J.Biol. Chem. (U.S.), 271(37):22522 (1996). Other studies reporting on thebiological functions of proteins having leucine rich repeats include:Tayar, N., et al., Mol. Cell Endocrinol., (Ireland), 125(1-2):65-70(December 1996) (gonadotropin receptor involvement); Miura, Y., et al.,Nippon Rinsho (Japan), 54(7):1784-1789 (July 1996) (apoptosisinvolvement); Harris, P. C., et al., J. Am. Soc. Nephrol.,6(4):1125-1133 (October 1995) (kidney disease involvement).

[0198] Efforts are therefore being undertaken by both industry andacademia to identify new proteins having leucine rich repeats to betterunderstand protein-protein interactions. Of particular interest arethose proteins having leucine rich repeats and identity or similarity toknown proteins having leucine rich repeats such as ALS. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel secreted and membrane-boundproteins having leucine rich repeats. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)].

[0199] 62. PRO531

[0200] Cadherins are a large family of transmembrane proteins. Cadherinscomprise a family of calcium-dependent glycoproteins that function inmediating cell-cell adhesion in virually all solid tissues ofmulticellular organisms. At least cadherins 1-13 as well as types B, E,EP, M, N, P and R have been characterized. Among the functions cadherinsare known for, with some exceptions, cadherins participate in cellaggregation and are associated with cell-cell adhesion sites. Recently,it has been reported that while all cadherins share multiple repeats ofa cadherin specific motif believed to correspond to folding ofextracellular domains, members of the cadherin superfamily havedivergent structures and, possibly, functions. In particular it has beenreported that members of the cadherin superfamily are involved in signaltransduction. See, Suzuki, J. Cell Biochem., 61(4):531-542 (1996).Cadherins are further described in Tanihara, et al., J. Cell Sci.,107(6):1697-1704 (1994), Aberle, et al., J. Cell Biochem., 61(4):514-523(1996) and Tanihara, et al., Cell Adhes. Commun., 2(1):15-26 (1994).

[0201] Protocadherins are members of the cadherin superfamily which arehighly expressed in the brain. In some studies, protocadherins haveshown cell adhesion activity. See, Sano, et al., EMBO J.,12(6):2249-2256 (1993). However, studies have also shown that someprotocadherins, such as protocadherin 3 (also referred to as Pcdh3 orpc3), do not show strong calcium dependent cell aggregation activity.See, Sago, et al., Genomics, 29(3):631-640 (1995) for this study andfurther characteristics of Pedh3.

[0202] Therefore, novel members of the cadherin superfamily are ofinterest. More generally, all membrane-bound proteins and receptors areof interest. Such proteins can play an important role in the formation,differentiation and maintenance of multicellular organisms. The fate ofmany individual cells, e.g., proliferation, migration, differentiation,or interaction with other cells, is typically governed by informationreceived from other cells and/or the immediate environment. Thisinformation is often transmitted by secreted polypeptides (for instance,mitogenic factors, survival factors, cytotoxic factors, differentiationfactors, neuropeptides, and hormones) which are, in turn, received andinterpreted by diverse cell receptors or membrane-bound proteins. Suchmembrane-bound proteins and cell receptors include, but are not limitedto, cytokine receptors, receptor kinases, receptor phosphatases,receptors involved in cell-cell interactions, and cellular adhesinmolecules like selectins and integrins. For instance, transduction ofsignals that regulate cell growth and differentiation is regulated inpatby phosphorylation of various cellular proteins. Protein tyrosinekinases, enzymes that catalyze that process, can also act as growthfactor receptors. Examples include fibroblast growth factor receptor andnerve growth factor receptor.

[0203] Membrane-bound proteins and receptor molecules have variousindustrial applications, including as pharmaceutical and diagnosticagents. Receptor immunoadhesins, for instance, can be employed astherapeutic agents to block receptor-ligand interaction. Themembrane-bound proteins can also be employed for screening of potentialpeptide or small molecule inhibitors of the relevant receptor/ligandinteraction.

[0204] Efforts are therefore being undertaken by both industry andacademia to identify new, native membrane bound proteins, particularthose having sequence identity with protocadherins, especially 3 and 4.Many efforts are focused on the screening of mammian recombinant DNAlibraries to identify the coding sequences for novel membrane-boundproteins. Provided herein are the results of such efforts. 63. PRO534

[0205] Protein disulfide isomerase is an enzymatic protein which isinvolved in the promotion of correct refolding of proteins through theestablishment of correct disulfide bond formation. Protein disulfideisomerase was initially identified based upon its ability to catalyzethe renaturation of reduced denatured RNAse (Goldberger et al., J. Biol.Chem. 239:1406-1410 (1964) and Epstein et al., Cold Spring Harbor Symp.Quant. Biol. 28:439-449 (1963)). Protein disulfide isomerase has beenshown to be a resident enzyme of the endoplasmic reticulum which isretamed in the endoplasmic reticulum via a -KDEL or -HDEL amino acidsequence at its C-terminus. Protein disulfide isomerase and relatedproteins are further described in Laboissiere, et al., J. Biol. Chem.,270(47:28006-28009 (1995); Jeenes, et al., Gene, 193(2):151-156 (1997;Koivunen, et al., Genomics, 42(3):397-404 (1997); and Desilva, et al.,DNA Cell Biol., 15(1):9-16 (1996). These studies indicate the importanceof the identification of protein disulfide related proteins.

[0206] More generally, and also of interest are all novel membrane-boundproteins and receptors. Such proteins can play an important role in theformation, differentiation and maintenance of multicellular organisms.The fate of many individual cells, e.g., proliferation, migration,differentiation, or interaction with other cells, is typically governedby information received from other cells and/or the immediateenvironment. This information is often transmitted by secretedpolypeptides (for instance, mitogenic factors, survival factors,cytotoxic factors, differentiation factors, neuropeptides, and hormones)which are, in turn, received and interpreted by diverse cell receptorsor membrane-bound proteins. Such membrane-bound proteins and cellreceptors include, but are not limited to, cytokine receptors, receptorkinases, receptor phosphatases, receptors involved in cell-cellinteractions, and cellular adhesin molecules like selectins andintegrins. For instance, transduction of signals that regulate cellgrowth and differentiation is regulated in part by phosphorylation ofvarious cellular proteins. Protein tyrosine kinases, enzymes thatcatalyze that process, can also act as growth factor receptors. Examplesinclude fibroblast growth factor receptor and nerve growth factorreceptor.

[0207] Membrane-bound proteins and receptor molecules have variousindustrial applications, including as pharmaceutical and diagnosticagents. Receptor immunoadhesins, for instance, can be employed astherapeutic agents to block receptor-ligand interaction. Themembrane-bound proteins can also be employed for screening of potentialpeptide or small molecule inlubitors of the relevant receptor/ligandinteraction.

[0208] Given the importance of membrane bound proteins, efforts areunder way to identity novel membrane bound protems. Moreover, given theimportance of disulfide bond-forming enzymes and their potential uses ina number of different applications, for example in increasing the yieldof correct refolding of recombinantly produced proteins, efforts arecurrently being undertaken by both industry and academia to identifynew, native proteins having sequence identity with protein disulfideisomerase. Many of these efforts are focused on the screening ofmammalian recombinant DNA libraries to identify the coding sequences fornovel protein disulfide isomerase homologs. We herein describe a novelpolypeptide having sequence identity with protein disulfide isomeraseand the nucleic acids encoding the same.

[0209] 64. PRO697

[0210] Secreted frizzled related proteins (sFRPs) are related to thefizzled family of transmembrane receptors. The sFRPs are approximately30 kDa in size, and each contains a putative signal sequence, afrizzled-like cysteine-rich domain, and a conserved hydrophiliccarboxy-terminal domain. It has been reported that sFRPs may function tomodulate Wnt signaling, or function as ligands for certain receptors.Ratner, et al., PNAS USA, 94(7):2859-2863 (1997). Therefore, sFRPs andproteins having sequence identity and/or similarity to sFRPs are ofinterest.

[0211] Another secreted protein of interest is any member of the familyof secreted apoptosis-related proteins (SARPs). Expression of SARPsmodifies the intracellular levels of beta-catenin, suggesting that SARPsinterfere with the Wnt-frizzled proteins signaling pathway. Melkonyan,et al., PNAS USA, 94(25):13636-13641 (1997). Therefore, SARPs andproteins having sequence identity and/or similarity to SARPs are ofinterest.

[0212] In addition to sFRPs and SARPs, many extracellular proteins areof interest. Extracellular proteins play an important role in theformation, differentiation and maintenance of multicellular organisms.The fate of many individual cells, e.g., proliferation, migration,differentiation, or interaction with other cells, is typically governedby information received from other cells and/or the immediateenvironment. This information is often transmitted by secretedpolypeptides (for instance, mitogenic factors, survival factors,cytotoxic factors, differentiation factors, neuropeptides, and hormones)which are, in turn, received and interpreted by diverse cell receptorsor membrane-bound proteins. These secreted polypeptides or signalingmolecules normally pass through the cellular secretory pathway to reachtheir site of action in the extracellular environment.

[0213] Secreted proteins have various industrial applications, includingpharmaceuticals, diagnostics, biosensors and bioreactors. Most proteindrugs available at present, such as thrombolytic agents, interferons,interleukins, erythropoietins, colony stimulating factors, and variousother cytokines, are secretory proteins. Their receptors, which aremembrane proteins, also have potential as therapeutic or diagnosticagents.

[0214] Efforts are being undertaken by both industry and academia toidentify new, native secreted proteins, particularly those havingsequence identity or similarity with sFRP-2 and SARP-1. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel secreted proteins. Examples ofscreening methods and techniques are described in the literature [see,for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996);U.S. Pat. No. 5,536,637)].

[0215] 65. PRO717

[0216] Efforts are being undertaken by both industry and academia toidentify new, native transmembrane receptor proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel receptor proteins. The resultsof such efforts are provided herein.

[0217] 66. PRO731

[0218] Cadherins are a large family of transmembrane proteins. Cadherinscomprise a family of calcium-dependent glycoproteins that function inmediating cell-cell adhesion in virtually all solid tissues ofmulticellular organisms. At least cadherins 1-13 as well as types B, E,EP, M, N, P and R have been characterized. Among the functions cadherinsare known for, with some exceptions, cadherins participate in cellaggregation and are associated with cell-cell adhesion sites. Recently,it has been reported that while all cadherins share multiple repeats ofa cadherin specific motif believed to correspond to folding ofextracellular donains, members of the cadherin superfamily havedivergent structures and, possibly, functions. In particular it has beenreported that members of the cadherin superfamily are involved in signaltransduction. See, Suzuki, J. Cell Biochem., 61(4):531-542 (1996).Cadherins are further described in Tanihara, et al., J. Cell Sci.,107(6):1697-1704 (1994), Aberle, et al., J. Cell Biochem., 61(4):514-523(1996) and Tanihara, et al., Cell Adhes. Commun., 2(1):15-26 (1994).

[0219] Protocadherins are members of the cadherin superfamily which arehighly expressed in the brain. In some studies, protocadherins haveshown cell adhesion activity. See, Sano, et al., EMBO J.,12(6):2249-2256 (1993). However, studies have also shown that someprotocadherins, such as protocadherin 3 (also referred to as Pcdh3 orpc3), do not show strong calcium dependent cell aggregation activity.See, Sago, et al., Genomics, 29(3):631-640 (1995) for this study andfurther characteristics of Pcdh3.

[0220] Therefore, novel members of the cadherin superfamily are ofinterest. More generally, all membrane-bound proteins and receptors areof interest. Such proteins can play an important role in the formation,differentiation and maintenance of multicellular organisms. The fate ofmany individual cells, e.g., proliferation, migration, differentiation,or interaction with other cells, is typically governed by informationreceived from other cells and/or the immediate environment. Thisinformation is often transmitted by secreted polypeptides (for instance,mitogenic factors, survival factors, cytotoxic factors, differentiationfactors, neuropeptides, and hormones) which are, in turn, received andinterpreted by diverse cell receptors or membrane-bound proteins. Suchmembrane-bound proteins and cell receptors include, but are not limitedto, cytokine receptors, receptor kinases, receptor phosphatases,receptors involved in cell-cell interactions, and cellular adhesinmolecules like selectins and integrins. For instance, transduction ofsignals that regulate cell growth and differentiation is regulated inpart by phosphorylation of various cellular proteins. Protein tyrosinekinases, enzymes that catalyze that process, can also act as growthfactor receptors. Examples include fibroblast growth factor receptor andnerve growth factor receptor.

[0221] Membrane-bound proteins and receptor molecules have variousindustrial applications, including as pharmaceutical and diagnosticagents. Receptor immunoadhesins, for instance, can be employed astherapeutic agents to block receptor-ligand interaction. Themembrane-bound proteins can also be employed for screening of potentialpeptide or small molecule inhibitors of the relevant receptor/ligandinteraction.

[0222] Efforts are therefore being undertaken by both industry andacademia to identify new, native membrane bound proteins, particularthose having sequence identity with protocadherins, especially 4, 68,43, 42, 3 and 5. Many efforts are focused on the screening of mammalianrecombinant DNA libraries to identify the coding sequences for novelmembrane-bound proteins. Provided herein are the results of suchefforts.

[0223] 67. PRO218

[0224] Efforts are being undertaken by both industry and academia toidentify new, native membrane bound proteins, particularly those havingsequence identity with membrane regulator proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel receptor proteins.

[0225] 68. PRO768

[0226] The integnns comprise a supergene family of cell-surfaceglycoprotein receptors that promote cellular adhesion. Each cell hasnumerous receptors that define its cell adhesive capabilities. Integrinsare involved in a wide variety of interaction between cells and othercells or matrix components. The integrins are of particular importancein regulating movement and function of immune system cells. The plateletIIb/IIIA integrin complex is of particular importance in regulatingplatelet aggregation. A member of the integrin family, integrin β-6, isexpressed on epithelial cells and modulates epithelial inflammation.Another integrin, leucocyte-associated antigen-1 (LFA-1) is important inthe adhesion of lymphocytes during an immune response.

[0227] Of particular interest is H36-alpha 7, an integrin alpha chainthat is developmentally regulated during myogenesis as described inSong, et al., J. Cell Biol., 117(3):643-657 (1992). The expressionpattern of the laminin-binding alpha 7 beta 1 integrin isdevelopmentally regulated in skeletal, cardiac, and smooth muscle.Ziober, et al., Mol. Biol. Cell, 8(9):1723-1734 (1997). It has beenreported that expression of the alpha 7-X1/X2 integrin is a novelmechanism that regulates receptor affinity states in a cell-specificcontext and may modulate integrin-dependent events during muscledevelopment and repair. Id. It has further been reported that lamininspromote the locomotion of skeletal myoblasts via the alpha 7 integrinreceptor. In particular it was reported that alpha 7 beta 1 receptor canpromote myoblast adhesion and motility on a restricted number of lamininisoforms and may be important in myogenic precursor recruitment duringregeneration and differentiation. Yao, et al., J. Cell Sci.,109(13):3139-3150 (1996). Spliced variants of integrin alpha 7 are alsodescribed in Leung, et al., Biochem. Biophys. Res. Commun.,243(1):317-325 (1998) and Fornaro and Languino, Matrix Biol.,16(4):185-193 (1997). Moreover, it has been reported that absence ofintegrin alpha 7 causes a form of muscular dystrophy. Thus integrins,particularly those related to integrin 7 and related molecules, are ofinterest.

[0228] In addition to the interest of integrins, more generally, allmembrane-bound proteins and receptors are of interest since suchproteins can play an important role in the formation, differentiationand maintenance of multicellular organisms. The fate of many individualcells, e.g., proliferation, migration, differentiation, or interactionwith other cells, is typically governed by information received fromother cells and/or the immediate environment. This information is oftentransmitted by secreted polypeptides (for instance, mitogenic factors,survival factors, cytotoxic factors, differentiation factors,neuropeptides, and hormones) which are, in turn, received andinterpreted by diverse cell receptors or membrane-bound proteins. Suchmembrane-bound proteins and cell receptors include, but are not limitedto, cytokine receptors, receptor kinases, receptor phosphatases,receptors involved in cell-cell interactions, and cellular adesinmolecules like selectins and integrins. For instance, transduction ofsignals that regulate cell growth and differentiation is regulated inpart by phosphorylation of various cellular proteins. Protein tyrosinekinases, enzymes that catalyze that process, can also act as growthfactor receptors. Examples include fibroblast growth factor receptor andnerve growth factor receptor.

[0229] Membrane-bound proteins and receptor molecules have variousindustrial applications, including as pharmaceutical and diagnosticagents. Receptor immunoadhesins, for instance, can be employed astherapeutic agents to block receptor-ligand interaction. Themembrane-bound proteins can also be employed for screening of potentialpeptide or small molecule inhibitors of the relevant receptor/ligandinteraction.

[0230] Therefore, efforts are being undertaken by both industry andacademia to identify new, native receptor proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel receptor proteins. The resultsof such efforts, particularly those focused on identifying newpolypeptides having sequence identity with integrins, are providedherein.

[0231] 69. PRO771

[0232] Testican is a multidomain testicular proteoglycan which isexpressed in numerous tissue types including, but not limited toneuromuscular tissue, the brain and reproductive tissues. Testicanresembles modulators of cell social behavior such as the regulation ofcell shape, adhesion, migration and proliferation. [Bonnet, F. et al.,J. Biol. Chem., 271(8):4373 (1996), Perin, J. P. et al., EXS(Switzerland), 70:191(1994), Alliel, P. M., et al, Eur. J. Biochem.,214(1):346 (1993), Charbonnier, F., et al., C. R. Seances Soc. Biol.Fil. (France), 191(1): 127 (1997)]. Among other reasons, since testicanhas been implicated in neuronal processes and may be associated with thegrowth of connective tissue, testican and related molecules are ofinterest.

[0233] More generally, all extracellular proteins are of interest.Extracellular proteins play an important role in the formation,differentiation and maintenance of multicellular organisms. The fate ofmany individual cells, e.g., proliferation, migration, differentiation,or interaction with other cells, is typically governed by informationreceived from other cells and/or the immediate environment. Thisinformation is often transmitted by secreted polypeptides (for instance,mitogenic factors, survival factors, cytotoxic factors, differentiationfactors, neuropeptides, and hormones) which are, in turn, received andinterpreted by diverse cell receptors or membrane-bound proteins. Thesesecreted polypeptides or signaling molecules normally pass through thecellular secretory pathway to reach their site of action in theextracellular environment.

[0234] Secreted proteins have various industrial applications, includingpharmaceuticals, diagnostics, biosensors and bioreactors. Most proteindrugs available at present, such as thrombolytic agents, interferons,interleukins, erythropoietins, colony stimulating factors, and variousother cytokines, are secretory proteins. Their receptors, which aremembrane proteins, also have potential as therapeutic or diagnosticagents. Efforts are being undertaken by both industry and academia toidentify new, native secreted proteins. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel secreted proteins. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)]. The results of such efforts, particularly those focused onidentifying molecules having identity and/or similarity with testicanare of interest.

[0235] 70. PRO733

[0236] T1/ST2 is a receptor-like molecule homologous to the type Iinterleukin-1 receptor, believed to be involved in cell signaling. TheT1/ST2 receptor and/or putative ligands are further described in Gayle,et al., J. Biol. Chem., 271(10):5784-5789 (1996), Kumar, et al., J.Biol. Chem., 270(46):27905-27913 (1995), and Mitcham, et al., J. Biol.Chem., 271(10):5777-5783 (1996). These proteins, and proteins relatedthereto are of interest.

[0237] More generally all membrane-bound proteins and receptors are ofinterest since they can play an important role in the formation,differentiation and maintenance of multicellular organisms. The fate ofmany individual cells, e.g., proliferation, migration, differentiation,or interaction with other cells, is typically governed by informationreceived from other cells and/or the immediate environment. Thisinformation is often transmitted by secreted polypeptides (for instance,mitogenic factors, survival factors, cytotoxic factors, differentiationfactors, neuropeptides, and hormones) which are, in turn, received andinterpreted by diverse cell receptors or membrane-bound proteins. Suchmembrane-bound proteins and cell receptors include, but are not limitedto, cytokine receptors, receptor kinases, receptor phosphatases,receptors involved in cell-cell interactions, and cellular adhesinmolecules like selectins and integrins. For instance, transduction ofsignals that regulate cell growth and differentiation is regulated inpart by phosphorylation of various cellular proteins. Protein tyrosinekinases, enzymes that catalyze that process, can also act as growthfactor receptors. Examples include fibroblast growth factor receptor andnerve growth factor receptor.

[0238] Membrane-bound proteins and receptor molecules have variousindustrial applications, including as pharmaceutical and diagnosticagents. Receptor immunoadhesins, for instance, can be employed astherapeutic agents to block receptor-ligand interaction. Themembrane-bound proteins can also be employed for screening of potentialpeptide or small molecule inhibitors of the relevant receptor/ligandinteraction.

[0239] Efforts are being undertaken by both industry and academia toidentify new, native receptor proteins. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel receptor proteins. The results of such efforts areprovided herein.

[0240] 71. PRO162

[0241] Pancreatitis-associated protein (PAP) is a secretory protein thatis overexpressed by the panscreas during acute pancreatitis. Serum PAPconcentrations have been shown to be abnormally high in patients withacute pancreatitis. Pezzilli et al., Am. J. Gastroenterol.,92(10):1887-1890 (1997).

[0242] PAP is synthesized by the pancreas due to pancreatic inflammationand has been shown to be a good serum marker for injury of the pancreas.In addition, serum PAP levels appear to strongly correlate withcreatinine clearance measurements. In patients with a pancreas-kidneytransplantation, PAP may prove to be a useful biological andhistological marker of pancreatic graft rejection. Van der Pijl et al.,Transplantation, 63(7):995-1003 (1997). Further, PAP has been shown tobe useful in screening neonates for cystic fibrosis. In fact, PAP maydiscriminate cystic fibrosis neonates with better specificity than thecurrent immunoreactive trypsis assay. Iovanna et al., C. R. Acad. Aci.III, 317(6):561-564.

[0243] Secreted proteins such as PAP have various industrialapplications, including pharmaceuticals, diagnostics, biosensors andbioreactors. Most protein drugs available at present, such asthrombolytic agents, interferons, interleukins, erythropoietins, colonystimulating factors, and various other cytokines, are secretoryproteins. Their receptors, which are membrane proteins, also havepotential as therapeutic or diagnostic agents.

[0244] Efforts are being undertaken by both industry and academia toidentify new, native secreted proteins. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel secreted proteins. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci. 93:7108-7113 (1996); U.S. Pat. No.5,536,637)]. The results of such efforts are presented herein.

[0245] 72. PRO788

[0246] Anti-neoplastic urinary protein (ANUP) was identified as themajor protein present in a fraction of human urine which exhibitsantiproliferative activity against human tumor cell lines withoutaffecting the growth of several normal diploid cell lines or tumor cellsof mouse or hamster origin. Sloane et al., Biochem. J., 234(2):355-362(1986).

[0247] ANUP is a unique cytokine that has been found in humangranulocytes. The N-terminal amino acid sequence has been shown to beunique. A synthetic peptide corresponding to the first nine residues,with Cys at positions 4 and 7, was found to be an anti-tumor agent invitro. Ridge and Sloane, Cytokine, 8(1):1-5 (1996).

[0248] Secreted proteins such as ANUP have various industrialapplications, including pharmaceuticals, diagnostics, biosensors andbioreactors. Most protein drugs available at present, such asthrombolytic agents, interferons, interleukins, erythropoietins, colonystimulating factors, and various other cytokines, are secretoryproteins. Their receptors, which are membrane proteins, also havepotential as therapeutic or diagnostic agents. Efforts are beingundertaken by both industry and academia to identify new, nativesecreted proteins. Many efforts are focused on the screening ofmammalian recombinant DNA libraries to identify the coding sequences fornovel secreted proteins. Examples of screening methods and techniquesare described in the literature [see, for example, Klein et al., Proc.Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

[0249] 73. PRO1008

[0250] Dickkopf-1 (dkk-1) is a member of a family of secreted proteinsand functions in head induction. Dkk-1 is an inducer of Spemannorganizer in amphibian embryos. Glinka, et al., Nature,391(6665):357-362 (1998). Dkk-1 is a potent antagonist of Wntsignalling, suggesting that dkk genes encode a family of secreted Wntinhibitors. Thus, dkk-1 family members and related molecules are ofinterest.

[0251] More generally, all extracellular proteins are of interest sincethey can play an important role in the formation, differentiation andmaintenance of multicellular organisms. The fate of many individualcells, e.g., proliferation, migration, differentiation, or interactionwith other cells, is typically governed by information received fromother cells and/or the immediate environment. This information is oftentransmitted by secreted polypeptides (for instance, mitogenic factors,survival factors, cytotoxic factors, differentiation factors,neuropeptides, and hormones) which are, in turn, received andinterpreted by diverse cell receptors or membrane-bound proteins. Thesesecreted polypeptides or signaling molecules normally pass through thecellular secretory pathway to reach their site of action in theextracellular environment.

[0252] Secreted proteins have various industrial applications, includingpharmaceuticals, diagnostics, biosensors and bioreactors. Most proteindrugs available at present, such as thrombolytic agents, interferons,interleukins, erythropoietins, colony stimulating factors, and variousother cytokines, are secretory proteins. Their receptors, which aremembrane proteins, also have potential as therapeutic or diagnosticagents.

[0253] Efforts are being undertaken by both industry and academia toidentify new, native secreted proteins, particularly those related todkk-1. Many efforts are focused on the screening of mammalianrecombinant DNA libraries to identify the coding sequences for novelsecreted proteins. Examples of screening methods and techniques aredescribed in the literature [see, for example, Klein et al., Proc. Natl.Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)]. The resultsof such efforts to identify molecules related to dkk-1 are providedherein.

[0254] 74. PRO1012

[0255] Protein disulfide isomerase is an enzymatic protein which isinvolved in the promotion of correct refolding of proteins through theestablishment of correct disulfide bond formation. Protein disulfideisomerase was initially identified based upon its ability to catalyzethe renaturation of reduced denatured RNAse (Goldberger et al., J. Biol.Chem. 239:1406-1410 (1964) and Epstein et al., Cold Spring Harbor Symp.Quant. Biol. 28:439-449 (1963)). Protein disulfide isomerase has beenshown to be a resident enzyme of the endoplasmic reticulum which isretained in the endoplasmic reticulum via a -KDEL or -HDEL amino acidsequence at its C-terninus. Protein disulfide isomerase and relatedproteins are further described in Laboissiere, et al., J. Biol. Chem.,270(47:28006-28009 (1995); Jeenes, et al., Gene, 193(2):151-156 (1997;Koivunen, et al., Genomics, 42(3):397-404 (1997); and Desilva, et al.,DNA Cell Biol., 15(1):9-16 (1996). These studies indicate the importanceof the identification of protein disulfide related proteins.

[0256] More generally, the identification of all extracellular andmembrane-bound proteins is of interest since they play important rolesin the formation, differentiation and maintenance of multicellularorganisms. The fate of many individual cells, e.g., proliferation,migration, differentiation, or interaction with other cells, istypically governed by information received from other cells and/or theimmediate environment. This information is often transmitted by secretedpolypeptides (for instance, mitogenic factors, survival factors,cytotoxic factors, differentiation factors, neuropeptides, and hormones)which are, in turn, received and interpreted by diverse cell receptorsor membrane-bound proteins. These secreted polypeptides or signalingmolecules normally pass through the cellular secretory pathway to reachtheir site of action in the extracellular environment, usually at amembrane-bound receptor protein.

[0257] Secreted proteins have various industrial applications, includinguse as pharmaceuticals, diagnostics, biosensors and bioreactors. Infact, most protein drugs available at present, such as thrombolyticagents, interferons, interleukins, erythropoietins, colony stimulatingfactors, and various other cytokines, are secretory proteins. Theirreceptors, which are membrane-bound proteins, also have potential astherapeutic or diagnostic agents. Receptor immunoadhesins, for instance,can be employed as therapeutic agents to block receptor-ligandinteraction. Membrane-bound proteins can also be employed for screeningofpotential peptide or small molecule inhibitors of the relevantreceptor/ligand interaction. Such membrane-bound proteins and cellreceptors include, but are not limited to, cytokine receptors, receptorkinases, receptor phosphatases, receptors involved in cell-cellinteractions, and cellular adhesin molecules like selectins andintegrins. Transduction of signals that regulate cell growth anddifferentiation is regulated in part by phosphorylation of variouscellular proteins. Protein tyrosine kinases, enzymes that catalyze thatprocess, can also act as growth factor receptors. Examples includefibroblast growth factor receptor and nerve growth factor receptor.

[0258] Of particular interest are cellular proteins having endoplasmicreticulum (ER) retention signals. These proteins are retained in thecell and function closely with endoplasmic reticulum in proteinproduction. Such proteins have been described previously, i.e., seeShorrosh and Dixon, Plant J., 2(1):51-58 (1992).

[0259] Efforts are being undertaken by both industry and academia toidentify new, native secreted and membrane-bound receptor proteins, andin particular, cellular proteins having ER retension signals. Manyefforts are focused on the screening of mammalian recombinant DNAlibraries to identify the coding sequences for novel secreted andmembrane-bound receptor proteins. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)]. The results of such efforts, particularly theidentification of novel polypeptides and nucleic acids encoding thesame, which have sequence identity and similarity to protein disulfideisomerase are presented herein.

[0260] 75. PRO1014

[0261] Oxygen free radicals and antioxidants appear to play an importantrole in the central nervous system after cerebral ischemia andreperfusion. Moreover, cardiac injury, related to ischaemia andreperfusion has been reported to be caused by the action of freeradicals. Additionally, studies have reported that the redox state ofthe cell is a pivotal determinant of the fate of the cells. Furthermore,reactive oxygen species have been reported to be cytotoxic, causinginflammatory disease, including tissue necrosis, organ failure,atherosclerosis, infertility, birth defects, premature aging, mutationsand malignancy. Thus, the control of oxidation and reduction isimportant for a number of reasons including for control and preventionof strokes, heart attacks, oxidative stress and hypertension. In thisregard, reductases, and particularly, oxidoreductases, are of interest.Publications further describing this subject matter include Kelsey, etal., Br. J. Cancer, 76(7):852-4 (1997); Friedrich and Weiss, J. Theor.Biol., 187(4):529-40 (1997) and Pieulle, et al., J. Bacteriol.,179(18):5684-92 (1997).

[0262] In addition to reductases in particular, novel polypeptides aregenerally of interest. Extracellular proteins play an important role inthe formation, differentiation and maintenance of multicellularorganisms. The fate of many individual cells, e.g., proliferation,migration, differentiation, or interaction with other cells, istypically governed by information received from other cells and/or theimmediate environment. This information is often transmitted by secretedpolypeptides (for instance, mitogenic factors, survival factors,cytotoxic factors, differentiation factors, neuropeptides, and hormones)which are, in turn, received and interpreted by diverse cell receptorsor membrane-bound proteins. These secreted polypeptides or signalingmolecules normally pass through the cellular secretory pathway to reachtheir site of action in the extracellular environment.

[0263] Secreted proteins have various industrial applications, includingpharmaceuticals, diagnostics, biosensors and bioreactors. Most proteindrugs available at present, such as thrombolytic agents, interferons,interleukins, erythropoietins, colony stimulating factors, and variousother cytokines, are secretory proteins. Their receptors, which aremembrane proteins, also have potential as therapeutic or diagnosticagents. Efforts are being undertaken by both industry and academia toidentify new, native secreted proteins. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel secreted proteins. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)]. The results of such efforts, particularly those identifyingpolypeptides having sequence identity with reductases, and the nucleicacids encoding the same, are presented herein.

[0264] 76. PRO1017

[0265] Enzymatic proteins play important roles in the chemical reactionsinvolved in the digestion of foods, the biosynthesis of macromolecules,the controlled release and utilization of chemical energy, and otherprocesses necessary to sustain life. Sulfotransferases are enzymes whichtransfer sulfate from a sulfate donor to acceptor substrates,particularly those containing terminal glucoronic acid. The HNK-1carbohydrate epitope is expressed on several neural adhesionglycoproteins and a glycolipid, and is involved in cell interactions.The glucuronyltransferase and sulfotransferase are considered to be thekey enzymes in the biosynthesis of this epitope because the rest of thestructure occurs often in glycoconjugates. HNK-1 sulfotransfererase isfurther described in Bakker, H., et al., J. Biol. Chem.,272(47):29942-29946 (1997).

[0266] In addition to HNK-1 sulfotransfererase, and novel proteinsrelated thereto, all novel proteins are of interest. Extracellular andmembrane-bound proteins play important roles in the formation,differentiation and maintenance of multicellular organisms. The fate ofmany individual cells, e.g., proliferation, migration, differentiation,or interaction with other cells, is typically governed by informationreceived from other cells and/or the immediate environment. Thisinformation is often transmitted by secreted polypeptides (for instance,mitogenic factors, survival factors, cytotoxic factors, differentiationfactors, neuropeptides, and hormones) which are, in turn, received andinterpreted by diverse cell receptors or membrane-bound proteins. Thesesecreted polypeptides or signaling molecules normally pass through thecellular secretory pathway to reach their site of action in theextracellular environment, usually at a membrane-bound receptor protein.

[0267] Secreted proteins have various industrial applications, includinguse as pharmaceuticals, diagnostics, biosensors and bioreactors. Infact, most protein drugs available at present, such as thrombolyticagents, interferons, interleukins, erythropoietins, colony stimulatingfactors, and various other cytokines, are secretory proteins. Theirreceptors, which are membrane-bound proteins, also have potential astherapeutic or diagnostic agents. Receptor immunoadhesins, for instance,canbe employed as therapeutic agents to block receptor-ligandinteraction. Membrane-bound proteins can also be employed for screeningof potential peptide or small molecule inhibitors of the relevantreceptor/ligand interaction. Such membrane-bound proteins and cellreceptors include, but are not limited to, cytokine receptors, receptorkinases, receptor phosphatases, receptors involved in cell-cellinteractions, and cellular adhesin molecules like selectins andintegrins. Transduction of signals that regulate cell growth anddifferentiation is regulated in part by phosphorylation of variouscellular proteins. Protein tyrosine kinases, enzymes that catalyze thatprocess, can also act as growth factor receptors. Examples includefibroblast growth factor receptor and nerve growth factor receptor.

[0268] Efforts are being undertaken by both industry and academia toidentify new, native secreted and membrane-bound receptor proteins,particularly those having sequence identity with HNK-1 sulfotransferase.Many efforts are focused on the screening of mammalian recombinant DNAlibraries to identify the coding sequences for novel secreted andmembrane-bound receptor proteins. Examples of screening methods andtechniques are described in the literature [see, for example, Klein etal., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)]. The results of such efforts are provided herein.

[0269] 77. PRO474

[0270] Enzymatic proteins play important roles in the chemical reactionsinvolved in the digestion of foods, the biosynthesis of macromolecules,the controlled release and utilization of chemical energy, and otherprocesses necessary to sustain life. Glucose dehydrogenase functions inthe oxidation of glucose to gluconate to generate metabolically usefulenergy. The regulation of the PQQ-linked glucose dehydrogenase indifferent organisms is reviewed in Neijssel, et al., Antonie VanLeeuwenhoek, 56(1):51-61 (1989). Glucose dehydrogenase functions as anauxiliary energy generating mechanism, because it is maximallysynthesized under conditions of energy stress. In addition to moleculesrelated to glucose dehydrogenase, all novel proteins are of interest.Extracellular and membrane-bound proteins play important roles in theformation, differentiation and maintenance of multicellular organisms.The fate of many individual cells, e.g., proliferation, migration,differentiation, or interaction with other cells, is typically governedby information received from other cells and/or the immediateenvironment. This information is often transmitted by secretedpolypeptides (for instance, mitogenic factors, survival factors,cytotoxic factors, differentiation factors, neuropeptides, and hormones)which are, in turn, received and interpreted by diverse cell receptorsor membrane-bound proteins. These secreted polypeptides or signalingmolecules normally pass through the cellular secretory pathway to reachtheir site of action in the extracellular environment, usually at amembrane-bound receptor protein.

[0271] Secreted proteins have various industrial applications, includinguse as pharmaceuticals, diagnostics, biosensors and bioreactors. Infact, most protein drugs available at present, such as thrombolyticagents, interferons, interleukins, erythropoietins, colony stimulatingfactors, and various other cytokines, are secretory proteins. Theirreceptors, which are membrane-bound proteins, also have potential astherapeutic or diagnostic agents. Receptor immunoadhesins, for instance,can be employed as therapeutic agents to block receptor-ligandinteraction. Membrane-bound proteins can also be employed for screeningof potential peptide or small molecule inhibitors of the relevantreceptor/ligand interaction. Such membrane-bound proteins and cellreceptors include, but are not limited to, cytokine receptors, receptorkinases, receptor phosphatases, receptors involved in cell-cellinteractions, and cellular adhesin molecules like selectins andintegrins. Transduction of signals that regulate cell growth anddifferentiation is regulated in part by phosphorylation of variouscellular proteins. Protein tyrosine kinases, enzymes that catalyze thatprocess, can also act as growth factor receptors. Examples includefibroblast growth factor receptor and nerve growth factor receptor.

[0272] Efforts are being undertaken by both industry and academia toidentify new, native secreted and membrane-bound receptor proteins, andparticularly cellular proteins and those related to dehydrogenase oroxidoreductase. Many efforts are focused on the screening of mammalianrecombinant DNA libraries to identify the coding sequences for novelsecreted and membrane-bound receptor proteins. Examples of screeningmethods and techniques are described in the literature [see, forexample, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S.Pat. No. 5,536,637)]. The results of such efforts are presented herein.

[0273] 78. PRO1031

[0274] It has been reported that the cytokine interleukin 17 (IL-17)stimulates epithelial, endothelial, and fibroblastic cells to secretecytokines such as IL-6, IL-8, and granulocyte-colony-stimulating factor,as well as prostaglandin E2. Moreover, it has been shown that whencultured in the presence of IL-17, fibroblasts could sustainproliferation of CD34+ preferential maturation into neutrophils. Thus ithas been suggested that IL-17 constitutes an early initiator of the Tcell-dependent inflammatory reaction and/or an element of the cytokinenetwork that bridges the immune system to hematopoiesis. See, Yao, etal., J. Immunol., 155(12):5483-5486 (1995); Fossiez, et al., J. Exp.Med., 183(6):2593-2603(1996); Kennedy, et al., J. Interferon CytokineRes., 16(8):611-617 (1996). Thus, proteins related to IL-17 are ofinterest.

[0275] More generally, all novel proteins are of interest. Extracellularproteins play an important role in the formation, differentiation andmaintenance of multicellular organisms. The fate of many individualcells, e.g., proliferation, migration, differentiation, or interactionwith other cells, is typically governed by information received fromother cells and/or the immediate environment. This information is oftentransmitted by secreted polypeptides (for instance, mitogenic factors,survival factors, cytotoxic factors, differentiation factors,neuropeptides, and hormones) which are, in turn, received andinterpreted by diverse cell receptors or membrane-bound proteins. Thesesecreted polypeptides or signaling molecules normally pass through thecellular secretory pathway to reach their site of action in theextracellular environment.

[0276] Secreted proteins have various industrial applications, includingpharmaceuticals, diagnostics, biosensors and bioreactors. Most proteindrugs available at present, such as thrombolytic agents, interferons,interleukins, erythropoietins, colony stimulating factors, and variousother cytokines, are secretory proteins. Their receptors, which aremembrane proteins, also have potential as therapeutic or diagnosticagents.

[0277] Efforts are being undertaken by both industry and academia toidentify new, native secreted proteins, particularly those related toIL-17. Many efforts are focused on the screening of mammalianrecombinant DNA libraries to identify the coding sequences for novelsecreted proteins. Examples of screening methods and techniques aredescribed in the literature [see, for example, Klein et al., Proc. Natl.Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)]. The resultsof such efforts are presented herein.

[0278] 79. PRO938

[0279] Protein disulfide isomerase is an enzymatic protein which isinvolved in the promotion of correct refolding of proteins through theestablishment of correct disulfide bond formation. Protein disulfideisomerase was initially identified based upon its ability to catalyzethe renaturation of reduced denatured RNAse (Goldberger et al., J. Biol.Chem. 239:1406-1410 (1964) and Epstein et al., Cold Spring Harbor Symp.Quant. Biol. 28:439-449 (1963)). Protein disulfide isomerase has beenshown to be a resident enzyme of the endoplasmic reticulum which isretained in the endoplasmic reticulum via a -KDEL or -HDEL amino acidsequence at its C-terminus. Protein disulfide isomerase and relatedproteins are further described in Laboissiere, et al., J. Biol. Chem.,270(47):28006-28009 (1995); Jeenes, et al., Gene, 193(2):151-156 (1997);Koivunen, et al., Genomics, 42(3:397-404 (1997); Desilva, et al., DNACell Biol., 15(1):9-16 (1996); Freedman, et al. Trends in Biochem. Sci.19:331-336 (1994); Bulleid, N. J. Advances in Prot. Chem. 44:125-50(1993); and Noiva, R., Prot. Exp. and Purification 5: 1-13 (1994). Thesestudies indicate the importance of the identification of proteindisulfide related proteins.

[0280] More generally, and also of interest are all novel membrane-boundproteins and receptors. Such proteins can play an important role in theformation, differentiation and maintenance of multicellular organisms.The fate of many individual cells, e.g., proliferation, migration,differentiation, or interaction with other cells, is typically governedby information received from other cells and/or the immediateenvironment. This information is often transmitted by secretedpolypeptides (for instance, mitogenic factors, survival factors,cytotoxic factors, differentiation factors, neuropeptides, and hormones)which are, in turn, received and interpreted by diverse cell receptorsor membrane-bound proteins. Such membrane-bound proteins and cellreceptors include, but are not limited to, cytokine receptors, receptorkinases, receptor phosphatases, receptors involved in cell-cellinteractions, and cellular adhesin molecules like selectins andintegrins. For instance, transduction of signals that regulate cellgrowth and differentiation is regulated in part by phosphorylation ofvarious cellular proteins. Protein tyrosine kinases, enzymes thatcatalyze that process, can also act as growth factor receptors. Examplesinclude fibroblast growth factor receptor and nerve growth factorreceptor.

[0281] Membrane-bound proteins and receptor molecules have variousindustrial applications, including as pharmaceutical and diagnosticagents. Receptor inmunoadhesins, for instance, canbe employed astherapeutic agents to block receptor-ligand interaction. Themembrane-bound proteins can also be employed for screening of potentialpeptide or small molecule inhibitors of the relevant receptor/ligandinteraction.

[0282] Given the importance of membrane bound proteins, efforts areunder way to identity novel membrane bound proteins. Moreover, given theimportance of disulfide bond-forming enzymes and their potential uses ina number of different applications, for example in increasing the yieldof correct refolding of recombinantly produced proteins, efforts arecurrently being undertaken by both industry and academia to identifynew, native proteins having sequence identity with protein disulfideisomerase. Many of these efforts are focused on the screening ofmammalian recombinant DNA libraries to identify the coding sequences fornovel protein disulfide isomerase homologs.

[0283] We herein describe the identification and characterization of anovel polypeptide having homology to protein disulfide isomerase.

[0284] 80. PRO1082

[0285] The low density lipoprotein (LDL) receptor is a membrane-boundprotein that plays a key role in cholesterol homeostasis, mediatingcellular uptake of lipoprotein particles by high affinity binding to itsligands, apolipoprotein (apo) B-100 and apoE. The ligand-binding domainof the LDL receptor contains 7 cysteine-rich repeats of approximately 40amino acids, wherein each repeat contains 6 cysteines, which form 3intra-repeat disulfide bonds. These unique structural features providethe LDL receptor with its ability to specifically interact with apoB-100 and apoE, thereby allowing for transport of these lipoproteinparticles across cellular membranes and metabolism of their components.Soluble fragments containing the extracellular domain of the LDLreceptor have been shown to retain the ability to interact with itsspecific lipoprotein ligands (Simmons et al., J. Biol. Chem.272:25531-25536 (1997)). LDL receptors are further described in Javitt,FASEB J., 9(13):1378-1381 (1995) and Herz and Willnow, Ann. NY Acad.Sci., 737:14-19 (1994). Thus, proteins having sequence identity with LDLreceptors are of interest.

[0286] More generally, all membrane-bound proteins and receptors canplay an important role in te formation, differentiation and maintenanceof multicellular organisms. The fate of many individual cells, e.g.,proliferation, migration, differentiation, or interaction with othercells, is typically governed by information received from other cellsand/or the immediate environment. This information is often transmittedby secreted polypeptides (for instance, mitogenic factors, survivalfactors, cytotoxic factors, differentiation factors, neuropeptides, andhormones) which are, in turn, received and interpreted by diverse cellreceptors or membrane-bound proteins. Such membrane-bound proteins andcell receptors include, but are not limited to, cytokine receptors,receptor kinases, receptor phosphatases, receptors involved in cell-cellinteractions, and cellular adhesin molecules like selectins andintegrins. For instance, transduction of signals that regulate cellgrowth and differentiation is regulated in part by phosphorylation ofvarious cellular proteins. Protein tyrosine kinases, enzymes thatcatalyze that process, can also act as growth factor receptors. Examplesinclude fibroblast growth factor receptor and nerve growth factorreceptor. Of particular interest are membrane bound proteins that havetype II transmembrane domains.

[0287] Membrane-bound proteins and receptor molecules have variousindustrial applications, including as pharmaceutical and diagnosticagents. Receptor immunoadhesins, for instance, can be employed astherapeutic agents to block receptor-ligand interaction. Themembrane-bound proteins can also be employed for screening of potentialpeptide or small molecule inhibitors of the relevant receptor/ligandinteraction.

[0288] Efforts are thus being undertaken by both industry and academiato identify new, native proteins, particularly membrane bound proteinsincluding type II transmembrane bound proteins. Many efforts are focusedon the screening of mammalian recombinant DNA libraries to identify thecoding sequences for novel receptor proteins. The results of suchefforts are provided herein.

[0289] 81. PRO1083

[0290] Of particular interest are membrane bound proteins that belong tothe seven transmembrane (7TM) receptor superfamily. Examples of thesereceptors include G-protein coupled receptors such as ion receptors.Another example of a 7TM receptor superfamily member is described inOsterhoff, et al., DNA Cell Biol., 16(4):379-389 (1997).

[0291] Membrane-bound proteins and receptor molecules have variousindustrial applications, including as pharmaceutical and diagnosticagents. Receptor immunoadhesins, for instance, can be employed astherapeutic agents to block receptor-ligand interaction. Themembrane-bound proteins can also be employed for screening of potentialpeptide or small molecule inhibitors of the relevant receptor/ligandinteraction.

[0292] Efforts are being undertaken by both industry and academia toidentify new, native receptor proteins. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identity the codingsequences for novel receptor proteins. The results of such efforts arepresented herein.

[0293] 82. PRO200

[0294] Polypeptides involved in survival, proliferation and/ordifferentiation of cells are of interest. Polypeptides known to beinvolved in the survival, proliferation and/or differentiation of cellsinclude VEGF and members of the bone morphogenetic protein family.Therefore, novel polypeptides which are related to either VEGF or thebone morphogenetic protein are of interest.

[0295] The heparin-binding endothelial cell-growth factor, VEGF, wasidentified and purified from media conditioned by bovine pituitaryfollicular or folliculo-stellate cells over several years ago. SeeFerrara et al., Biophys. Res. Comm. 161, 851 (1989). VEGF is a naturallyoccurring compound that is produced in follicular or folliculo-stellatecells (FC), a morphologically well characterized population of granularcells. The FC are stellate cells that send cytoplasmic processes betweensecretory cells.

[0296] VEGF is expressed in a variety of tissues as multiple homodimericforms (121, 165, 189 and 206 amino acids per monomer) resulting fromalternative RNA splicing. VEGF₁₂₁ is a soluble mitogen that does notbind heparin; the longer forms of VEGF bind heparin with progressivelyhigher affinity. The heparin-binding forms of VEGF can be cleaved in thecarboxy terminus by plasmin to release (a) diffusible form(s) of VEGF.Amino acid sequencing of the carboxy terminal peptide identified afterplasmin cleavage is Arg₁₁₀-Ala₁₁₁. Amino terminal “core” protein, VEGF(1-110) isolated as a homodimer, binds neutralizing monoclonalantibodies (4.6.1 and 2E3) and soluble forms of FMS-like tyrosine kinase(FLT-1), kinase domain region (KDR) and fetal liver kinase (FLK)receptors with similar affinity compared to the intact VEGF₁₆₅homodimer.

[0297] As noted, VEGF contains two domains that are responsiblerespectively for binding to the KDR and FLT-1 receptors. These receptorsexist only on endothelial (vascular) cells. As cells become depleted inoxygen, because of trauma and the like, VEGF production increases insuch cells which then bind to the respective receptors in order tosignal ultimate biological effect. The signal then increases vascularpermeability and the cells divide and expand to form new vascularpathways—vasculogenesis and angiogenesis.

[0298] Thus, VEGF is useful for treating conditions in which a selectedaction onthe vascular endothelial cells, in the absence of excessivetissue growth, is important, for example, diabetic ulcers and vascularinjuries resulting from trauma such as subcutaneous wounds. Being avascular (artery and venus) endothelial cell growth factor, VEGFrestores cells that are damaged, a process referred to asvasculogenesis, and stimulates the formulation of new vessels, a processreferred to as angiogenesis.

[0299] VEGF would also find use in the restoration of vasculature aftera myocardial infarct, as well as other uses that can be deduced. In thisregard, inhibitors of VEGF are sometimes desirable, particularly tomitigate processes such as angiogenesis and vasculogenesis in cancerouscells.

[0300] Regarding the bone morphogenetic protein family, members of thisfamily have been reported as being involved in the differentiation ofcartilage and the promotion of vascularization and osteoinduction inpreformed hydroxyapatite. Zou, et al., Genes Dev. (U.S.), 11(17):2191(1997); Levine, et al., Ann. Plast. Surg., 39(2):158 (1997). A number ofrelated bone morphogenetic proteins have been identified, all members ofthe bone morphogenetic protein (BMP) family. Bone morphogenetic nativeand mutant proteins, nucleic acids encoding therefor, related compoundsincluding receptors, host cells and uses are further described in atleast: U.S. Pat. Nos. 5,670,338; 5,454,419; 5,661,007; 5,637,480;5,631,142; 5,166,058; 5,620,867; 5,543,394; 4,877,864; 5,013,649;55,106,748; and 5,399,677. Of particular interest are proteins havinghomology with bone morphogenetic protein 1, a procollagen C-proteinasethat plays key roles in regulating matrix deposition.

[0301] The present invention is predicated upon research intended toidentify novel polypeptides which are related to VEGF and the BMPfamily, and in particular, polypeptides which have a role in thesurvival, proliferation and/or differentiation of cells. While the novelpolypeptides are not expected to have biological activity identical tothe known polypeptides to which they have homology, the knownpolypeptide biological activities can be used to determine the relativebiological activities of the novel polypeptides. In particular, thenovel polypeptides described herein can be used in assays which areintended to determine the ability of a polypeptide to induce survival,proliferation or differentiation of cells. In turn, the results of theseassays can be used accordingly, for diagnostic and therapeutic purposes.The results of such research is the subject of the present invention.

[0302] 83. PRO285 and PRO286

[0303] The cloning of the Toll gene of Drosophila, a maternal effectgene that plays a central role in the establishment of the embryonicdorsal-ventral pattern, has been reported by Hashimoto et al., Cell 52,269-279 (1988). The Drosophila Toll gene encodes an integral membraneprotein with an extracytoplasmic domain of 803 amino acids and acytoplasmic domain of 269 amino acids. The extracytoplasmic domain has apotential membrane-spanning segment, and contains multiple copies of aleucine-rich segment, a structural motif found in many transmembraneproteins. The Toll protein controls dorsal-ventral patterning inDrosophila embryos and activates the transcription factor Dorsal uponbinding to its ligand Spätzle. (Morisato and Anderson, Cell 76, 677-688(1994).) In adult Drosophila, the Toll/Dorsal signaling pathwayparticipates in the anti-fungal immune response. (Lenaitre et al., Cell86, 973-983 (1996).)

[0304] A human homologue of the Drosophila Toll protein has beendescribed by Medzhitov et al., Nature 388, 394-397 (1997). This humanToll, just as Drosophila Toll, is a type I transmembrane protein, withan extracellular domain consisting of 21 tandemly repeated leucine-richmotifs (leucine-rich region—LRR), separated by a non-LRR region, and acytoplasmic domain homologous to the cytoplasmic domain of the humaninterleulin-1 (IL-1) receptor. A constitutively active mutant of thehuman Toll transfected into human cell lines was shown to be able toinduce the activation of NF-κB and the expression of NF-KB-controlledgenes for the inflammatory cytokines IL-1, IL-6 and IL-8, as well as theexpression of the constimulatory molecule B7.1, which is required forthe activation of native T cells. It has been suggested that Tollfunctions in vertebrates as a non-clonal receptor of the immune system,which can induce signals for activating both an innate and an adaptiveimmune response in vertebrates. The human Toll gene reported byMedzlitov et al., supra was most strongly expressed in spleen andperipheral blood leukocytes (PBL), and the authors suggested that itsexpression in other tissues may be due to the presence of macrophagesand dendritic cells, in which it could act as an early-warning systemfor infection. The public GenBank database contains the following Tollsequences: Toll1 (DNAX# HSU88540-1, which is identical with the randomsequenced full-length cDNA #HUMRSC786-1); Toll2 (DNAX# HSU88878-1);Toll3 (DNAX# HSU88879-1); and Toll4 (DNAX# HSU88880-1, which isidentical with the DNA sequence reported by Medzhitov et al., supra). Apartial Toll sequence (Toll5) is available from GenBank under DNAX#HSU88881-1.

[0305] Further human homologues of the Drosophila Toll protein,designated as Toll-like receptors (huTLRs1-5) were recently cloned andshown to mirror the topographic structure of the Drosophila counterpart(Rock et al., Proc. Natl. Acad. Sci. USA 95, 588-593 [1998]).Overexpression of a constitutively active mutant of one human TLR(roll-protein homologue—Medzhitov et al., supra; TLR4—Rock et al.,supra) leads to the activation of NF-κB and induction of theinflamrnatory cytokines and constimulatory molecules. Medzhitov et al.,supra.

[0306] 84. PRO213-1, PRO1330 and PRO1449

[0307] Cancer is characterized by the increase in the number ofabnormal, or neoplastic, cells derived from a normal tissue whichproliferate to form a tumor mass, the invasion of adjacent tissues bythese neoplastic tumor cells, and the generation of malignant cellswhich eventually spread via the blood or lymphatic system to regionallymph nodes and to distant sites (metastasis). In a cancerous state acell proliferates under conditions in which normal cells would not grow.Cancer manifests itself in a wide variety of forms, characterized bydifferent degrees of invasiveness and aggressiveness.

[0308] Alteration of gene expression is intimately related to theuncontrolled cell growth and de-differentiation which are a commonfeature of all cancers. The genomes of certain well studied tumors havebeen found to show decreased expression of recessive genes, usuallyreferred to as tumor suppression genes, which would normally function toprevent malignant cell growth, and/or overexpression of certain dominantgenes, such as oncogenes, that act to promote malignant growth. Each ofthese genetic changes appears to be responsible for importing some ofthe traits that, in aggregate, represent the full neoplastic phenotype(Hunter, Cell 64, 1129 [1991]; Bishop, Cell 64, 235-248 [1991]).

[0309] A well known mechanism of gene (e.g. oncogene) overexpression incancer cells is gene amplification. This is a process where in thechromosome of the ancestral cell multiple copies of a particular geneare produced. The process involves unscheduled replication of the regionof chromosome comprising the gene, followed by recombination of thereplicated segments back into the chromosome (Alitalo et al., Adv.Cancer Res. 47, 235-281 [1986]). It is believed that the overexpressionof the gene parallels gene amplification, i.e. is proportionate to thenumber of copies made.

[0310] Proto-oncogenes that encode growth factors and growth factorreceptors have been identified to play important roles in thepathogenesis of various human malignancies, including breast cancer. Forexample, it has been found that the human ErbB2 gene (erbB2, also knownas her2, or c-erbB-2), which encodes a 185-kd transmembrane glycoproteinreceptor (p185HER2; HER2) related to the epidermal growth factorreceptor (EGFR), is overexpressed in about 25% to 30% of human breastcancer (Slamon et al., Science 235:177-182 [1987]; Slamon et al.,Science 244:707-712 [1989]).

[0311] It has been reported that gene amplification of a protooncogeneis an event typically involved in the more malignant forms of cancer,and could act as a predictor of clinical outcome (Schwab et al., GenesChromosomes Cancer 1, 181 -193 [1990]; Alitalo et al., supra). Thus,erbB2 overexpression is commonly regarded as a predictor of a poorprognosis, especially in patients with primary disease that involvesaxillary lymph nodes (Slamon et al., [1987] and [1989], supra; Ravdinand Chamness, Gene 159:19-27 [1995]; and Hynes and Stern, BiochemBiophys Acta 1198: 165-184 [1994]), and has been linked to sensitivityand/or resistance to hormone therapy and chemotherapeutic regimens,including CMF (cyclophosphamide, methotrexate, and fluoruracil) andanthracyclines (Baselga et al., Oncology 11 (3 Suppl 1): 43-48 [1997]).However, despite the association of erbB2 overexpression with poorprognosis, the odds of HER2-positive patients responding clinically totreatment with taxanes were greater than three times those ofHER2-negative patients (Ibid). A recombinant humanized anti-ErbB2(anti-HER2) monoclonal antibody (a humanized version of the murineanti-ErbB2 antibody 4D5, referred to as rhuMAb HER2 or Herceptin 7

) has been clinically active in patients with ErbB2-overexpressingmetastatic breast cancers that had received extensive prior anticancertherapy. (Baselga et al., J. Clin. Oncol. 14:737-744 [1996]).

[0312] The protein Notch and its homologues are key regulatory receptorsin determining the cell fate in various development processes. Theprotein Notch-4, also known as int-3 oncogene, was originally identifiedas a frequent target in mouse mammary tumor virus (MMVS). Notch-4 isbelieved to be a transgene which affects the differentiation capacity ofstem cells and leads to neoplastic proliferation in epithelial cells.Shirayoshi et al., Genes Cells 2(3): 213-224 (1997). Duringembryogenesis, the expression of Notch-4 was detected in endothelialcells of blood vessels forming tissues such as the dorsal aorta,intersegmental vessels, yolk sac vessels, cephalic vessels, heart,vessels inbranchial arches, and capillary plexuses. Notch-4 expressionin these tissues was also associated with flk-1, the major regulatorygene of vasculogenesis and angiogenesis. Notch-4 is also upregulated invitro during the differentiation of endothelial stem cell. Theendothelial cell specific expression pattern of Notch-4, as well as itsstructural similarity to Notch suggest that Notch-4 is an endothelialcell specific homologue of Notch and that it may play a role invaculogenesis and angiogenesis.

[0313] 85. PRO298

[0314] Efforts are being undertaken by both industry and academia toidentify new, native receptor proteins. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify the codingsequences for novel receptor proteins. We herein describe theidentification and characterization of novel transmembrane polypeptides,designated herein as PRO298 polypeptides.

[0315] 86. PRO337

[0316] Neuronal development in higher vertebrates is characterized byprocesses that must successfldly navigate distinct cellular environmenten route to their synaptic targets. The result is a functionally preciseformation of neural circuits. The precision is believed to result formmechanisms that regulate growth cone pathfmding and target recognition,followed by latter refinement and remodeling of such projections byevents that require neuronal activity, Goodman and Shatz, Cell/Neuron[Suppl.] 72(10): 77-98 (1993). It is further evident that differentneurons extend nerve fibers that are biochemically distinct and rely onspecific guidance cues provided by cell-cell, cell-matrix, andchemotrophic interactions to reach their appropriate synaptic targets,Goodman et al., supra.

[0317] One particular means by which diversity of the neuronal cellsurface may be generated is through differential expression of cellsurface proteins referred to as cell adhesion molecules (CAMs).Neuronally expressed CAMs have been implicated in diverse developmentalprocesses, including migration of neurons along radial glial cells,providing permissive or repulsive substrates for neurite extension, andin promoting the selective fasciculation of axons in projectionalpathways. Jessel, Neuron 1: 3-13 (1988); Edelman and Crossin, Annu. Rev.Biochem. 60: 155-190 (1991). Interactions between CAMs present on thegrowth cone membrane and molecules on opposing cell membranes or in theextracellular matrix are thought to provide the specific guidance cuesthat direct nerve fiber outgrowth along appropriate projectionalpathways. Such interactions are likely to result in the activation ofvarious second messenger systems within the growth cone that regulateneurite outgrowth. Doherty and Walsh, Curr. Opin Neurobiol. 2: 595-601(1992).

[0318] In higher vertebrates, most neural CAMs have been found to bemembers of three major structural families of proteins: the integrins,the cadherins, and the immunoglobulin gene superfamily (IgSF). Jessel,supra.; Takeichi, Annu. Rev. Biochem. 59: 237-252 (1990); Reichardt andTomaselli, Annu. Rev. Neurosci. 14: 531-570 (1991). Cell adhesionmolecules of the IgSF (or Ig-CAMs), in particular, constitute a largefamily of proteins frequently implicated in neural cell interactions andnerve fiber outgrowth during development, Salzer and Colman, Dev.Neurosci. 11: 377-390 (1989); Brümmendorf and Rathjen, J. Neurochem. 61:1207-1219 (1993). However, the majority of mammalian Ig-CAMs appear tobe too widely expressed to specify navigational pathways or synaptictargets suggesting that other CAMs, yet to be identified, have role inthese more selective interactions of neurons.

[0319] Many of the known neural Ig-CAMs have been found to be attachedto the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor.Additionally, many studies have implicated GPI-anchored proteins inproviding specific guidance cues during the outgrowth on neurons inspecific pathways. In studies of the grasshopper nervous system,treatment of embryos with phosphatidylinositol-specific phopholipase C(PIPLC), which selectively removes GPI-anchored proteins from thesurfaces of cells, resulted in misdirection and faulty navigation amongsubsets of pioneering growth cones, as well as inhibited migratorypatterns of a subset of early neurons, Chang et al., Devel. 114: 507-519(1992). The projection of retinal fibers to the optic tectum appears todepend, in part, on a 33 kDa GPI-anchored protein, however, the precisenature of this protein is unknown. Stahl et al., Neuron 5: 735-743(1990).

[0320] The expression of various GPI-anchored proteins has beencharacterized amongst the different populations of primary rat neuronsamongst dorsal root ganglion, sympathetic neurons of the cervicalganglion, sympathetic neurons of the superior cervical ganglion, andcerebellar granule neurons. Rosen et al., J. Cell Biol. 117: 617-627(1992). In contrast to the similar pattern of total membrane proteinexpression by these different types of neurons, striking differenceswere observed in the expression of GPI-anchored proteins between theseneurons. Recently, a 65 kDa protein band known as neurotrimin wasdiscovered and found to be differentially expressed by primary neurons(Rosen et al., supra), and restricted to the nervous system and found tobe the most abundant and earliest expressed of the GPI-anchored speciesin the CNS. Struyk et al., J. Neuroscience 15(3): 2141-2156 (1995). Thediscovery of neurotrimin has further lead to the identification of afamily of IgSF members, each containing three Ig-like domams that sharesignificant amino acid identity, now termed IgLON. Struyk et al., supra;Pimenta et al., Gene 170(2): 189-95 (1996).

[0321] Additional members of the IgLON subfamily include opiate bindingcell adhesion molecule (OBCAM), Schofield et al., EMBO J. 8: 489-495(1989); limbic associated membrane protein (LAMP), Pimenta et al.,supra; CEPU-1; GP55, Wilson et al., J. Cell Sci. 109: 3129-3138 (1996);Eur. J. Neurosci. 9(2): 334-41 (1997); and AvGp50, Hancox et al., BrainRes. Mol. Brain Res. 44(2): 273-85 (1997).

[0322] While the expression of neurotrimin appears to be widespread, itdoes appear to correlated with the development of several neuralcircuits. For example, between E18 and P10, neurotimin mRNA expressionwithin the forebrain is maintained at high levels in neurons of thedeveloping thalamus, cortical subplate, and cortex, particularly laminaeV and VI (with less intense expression in II, II, and IV, and minimalexpression in lamina I). Cortical subplate neurons may provide an early,temporary scaffold for the ingrowing thalamic afferents en route totheir final synaptic targets in the cortex. Allendoerfer and Shatz,Annu. Rev. Neurosci. 17: 185-218 (1994). Conversely, subplate neuronshave been suggested to be required for cortical neurons from layer V toselect VI to grow into the thalamus, and neurons from layer V to selecttheir targets in the colliculus, pons, and spinal cord (McConnell etal., J. Neurosci. 14: 1892-1907 (1994). The high level expression ofneurotrimin in many of these projections suggests that it could beinvolved in their development.

[0323] In the hindbrain, high levels of neurotrimin message expressionwere observed within the pontine nucleus and by the internal granulecells and Purkinje cells of the cerebellum. The pontine nucleus receivedafferent input from a variety of sources including corticopontine fibersof layer V, and is a major source of afferent input, via mossy fibers,to the granule cells which, in turn, are a major source of afferentinput via parallel fibers to Purkinje cells. [Palay and Chan-Palay, Thecerebellar cortex: cytology and organization. New York: Springer (1974].High level expression of neurotrimin these neurons again suggestspotential involvement in the establishment of these circuits.

[0324] Neurotrimin also exhibits a graded expression pattern in theearly postnatal striatum. Increased neurotrimin expression is foundoverlying the dorsolateral striatum of the rat, while lesserhybridization intensity is seen overlying the ventromedial striatum.Struyk et al., supra. This region of higher neurotrimin hybridizationintensity does not correspond to a cytoarchitecturally differentiableregion, rather it corresponds to the primary area of afferent input fromlayer VI of the contralateral sensorimotor cortex (Gerfen, Nature 311:461-464 (1984); Donoghue and Herkenham, Brain Res. 365: 397-403 (1986)).The ventromedial striatum, by contrast, receives the majority of itsafferent input from the perirhinal and association cortex. It isnoteworthy that a complementary graded pattern of LAMP expression, hasbeen observed within the striatium, with highest expression inventromedial regions, and lowest expression dorsolaterally. Levitt,Science 223: 299-301 (1985); Chesselet et al., Neuroscience 40: 725-733(1991).

[0325] 87. PRO403

[0326] Type II transmembrane proteins, also known as single passtransmembrane proteins have an N-terminal portion lodged in thecytoplasm while the C-terminal portion is exposed to the extracellulardomain.

[0327] Endothelin is a family of vasoconstrictor peptides about whichmuch activity has been focused to better understand its basicpharmacological, biochemical and molecular biological features,including the presence and structure of isopeptides and their genes(endothelin-1, −2 and û3), regulation of gene expression, intracellularprocessing, specific endothelin converting enzymes (ECE), receptorsubtypes (ET-A and ET-B), intracellular signal transduction followingreceptor activation, etc.

[0328] The endothelin (ET) family of peptides have potent vascular,cardiac and renal actions which may be of pathophysiological importancein many human disease states. ET-1 is expressed as an inactive 212 aminoacid prepropeptide. The prepropeptide is first cleaved at Arg52-Cys53and Arg92-Ala93 and then the carboxy terminal Lys91 and Arg92 aretrimmed from the protein to generate the propeptide big ET-1.

[0329] Endothelin is generated from inactive intermediates, the bigendothelins, by a unique processing event catalyzed by the zincmetalloprotease, endothelin converting enzyme (ECE). ECE was recentlycloned, and its structure was shown to be a single pass transmembraneprotein with a short intracellular N-terminal and a long extracellularC-terminal that contains the catalytic domain and numerousN-glycosylation sites. ECEs cleave the endothelin propeptide betweenTrp73 and Val74 producing the active peptide, ET, which appears tofunction as a local rather than a circulating hormone (Rubanyi, G. M. &Polokoff, M. A., Pharmachological Reviews 46: 325-415 (1994). Thus ECEactivity is a potential site of regulation of endothelin production anda possible target for therapeutic intervention inthe endothelin system.By blocking ECE activity, it is possible stop the production of ET-1 byinhibiting the conversion of the relatively inactive precursor, bigET-1, to the physiologically active form.

[0330] Endothelins may play roles in the pathophysiology of a number ofdisease states including: 1) cardiovascular diseases (vasospasm,hypertension, myocardial ischemia; reperfusion injury and acutemyochardial infarction, stroke (cerebral ischemia), congestive heartfailure, shock, atherosclerosis, vascular thickening); 2) kidney disease(acute and chronic renal failure, glomerulonephritis, cirrhosis); 3)lung disease (bronchial asthma, pulmonary hypertension); 4)gastrointestinal disorders (gastric ulcer, inflammatory bowel diseases);5) reproductive disorders (premature labor, dysmenorhea, preeclampsia)and 6) carcinogenesis. Rubanyi & Polokoff, supra.

SUMMARY OF THE INVENTION

[0331] 1. PRO213

[0332] Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO213”.

[0333] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO213 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO213polypeptide having amino acid residues 1 to 295 of FIG. 2 (SEQ ID NO:2),or is complementary to such encoding nucleic acid sequence, and remainsstably bound to it under at least moderate, and optionally, under highstringency conditions.

[0334] In another embodiment, the invention provides isolated PRO213polypeptide. In particular, the invention provides isolated nativesequence PRO213 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 295 of FIG. 2 (SEQ ID NO:2).

[0335] 2. PRO274

[0336] Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO274”.

[0337] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO274 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO274polypeptide having amino acid residues 1 to 492 of FIG. 4 (SEQ ID NO:7),or is complementary to such encoding nucleic acid sequence, and remainsstably bound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA39987-1184 vector deposited on Apr. 21, 1998as ATCC 209786 which includes the nucleotide sequence encoding PRO274.

[0338] In another embodiment, the invention provides isolated PRO274polypeptide. In particular, the invention provides isolated nativesequence PRO274 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 492 of FIG. 4 (SEQ ID NO:7). Anadditional embodiment of the present invention is directed to anisolated extracellular domain of a PRO274 polypeptide. Optionally, thePRO274 polypeptide is obtained or is obtainable by expressing thepolypeptide encoded by the cDNA insert of the DNA39987-1184 vectordeposited on Apr. 21, 1998 as ATCC 209786.

[0339] In another embodiment, the invention provides three expressedsequence tags (EST) comprising the nucleotide sequences of SEQ ID NO:8(herein designated as DNA17873), SEQ ID NO:9 (herein designated asDNA36157) and SEQ ID NO: 10 (herein designated as DNA28929) (see FIGS.5-7, respectively).

[0340] 3. PRO300

[0341] Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as “PRO300”.

[0342] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO300 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO300polypeptide having amino acid residues 1 to 457 of FIG. 9 (SEQ ID NO:19), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. The isolated nucleic acid sequence maycomprise the cDNA insert of the DNA40625-1189 vector deposited on Apr.21, 1998 as ATCC 209788 which includes the nucleotide sequence encodingPRO300.

[0343] In another embodiment, the invention provides isolated PRO300polypeptide. In particular, the invention provides isolated nativesequence PRO300 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 457 of FIG. 9 (SEQ ID NO:19). Anadditional embodiment of the present invention is directed to anisolated extracellular domain of a PRO300 polypeptide. Optionally, thePRO300 polypeptide is obtained or is obtainable by expressing thepolypeptide encoded by the cDNA insert of the DNA40625-1189 vectordeposited on Apr. 21, 1998 as ATCC 209788.

[0344] 4. PRO284

[0345] Applicants have identified a cDNA clone that encodes a noveltransmembrane polypeptide, wherein the polypeptide is designated in thepresent application as “PRO284”.

[0346] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO284 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO284polypeptide having amino acid residues 1 to 285 of FIG. 11 (SEQ IDNO:28), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO284 polypeptide having amino acidresidues about 25 to 285 of FIG. 11 (SEQ ID NO:28) or 1 or about 25 to Xof FIG. 11 (SEQ ID NO:28), where X is any amino acid from 71 to 80 ofFIG. 11 (SEQ ID NO:28), or is complementary to such encoding nucleicacid sequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions. The isolated nucleicacid sequence may comprise the cDNA insert of the DNA23318-1211 vectordeposited on Apr. 21, 1998 as ATCC 209787 which includes the nucleotidesequence encoding PRO284.

[0347] In another embodiment, the invention provides isolated PRO284polypeptide. In particular, the invention provides isolated nativesequence PRO284 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 285 of FIG. 11 (SEQ ID NO:28).Additional embodiments of the present invention are directed to isolatedPRO284 polypeptides comprising amino acids about 25 to 285 of FIG. 11(SEQ ID NO:28) or 1 or about 25 to X of FIG. 11 (SEQ ID NO:28), where Xis any amino acid from 71 to 80 of FIG. 11 (SEQ ID NO:28). Optionally,the PRO284 polypeptide is obtained or is obtainable by expressing thepolypeptide encoded by the cDNA insert of the DNA23318-1211 vectordeposited on Apr. 21, 1998 as ATCC 209787.

[0348] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA12982 which comprises thenucleotide sequence of SEQ ID NO:29.

[0349] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA15886 which comprises thenucleotide sequence of SEQ ID NO:30.

[0350] 5. PRO296

[0351] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to the sarcoma-amplified protein SAS,wherein the polypeptide is designated in the present application as“PRO296”.

[0352] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO296 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO296polypeptide having amino acid residues 1 to 204 of FIG. 15 (SEQ IDNO:36), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO296 polypeptide having amino acidresidues about 35 to 204 of FIG. 15 (SEQ ID NO:36) or amino acid 1 orabout 35 to X of FIG. 15 (SEQ ID NO:36), where X is any amino acid from42 to 51 of FIG. 15 (SEQ ID NO:36), or is complementary to such encodingnucleic acid sequence, and remains stably bound to it under at leastmoderate, and optionally, under high stringency conditions. The isolatednucleic acid sequence may comprise the cDNA insert of the DNA39979-1213vector deposited on Apr. 21, 1998 as ATCC 209789 which includes thenucleotide sequence encoding PR0296.

[0353] In another embodiment, the invention provides isolated PRO296polypeptide. In particular, the invention provides isolated nativesequence PRO296 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 204 of FIG. 15 (SEQ ID NO:36).Additional embodiments of the present invention are directed to PRO296polypeptides comprising amino acids about 35 to 204 of FIG. 15 (SEQ IDNO:36) or amino acid 1 or about 35 to X of FIG. 15 (SEQ ID NO:36), whereX is any amino acid from 42 to 51 of FIG. 15 (SEQ ID NO:36). Optionally,the PRO296 polypeptide is obtained or is obtainable by expressing thepolypeptide encoded by the cDNA insert of the DNA39979-1213 vectordeposited on Apr. 21, 1998 as ATCC 209789.

[0354] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA23020 comprising thenucleotide sequence of SEQ ID NO:37.

[0355] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA21971 comprising thenucleotide sequence of SEQ ID NO:38.

[0356] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA29037 comprising thenucleotide sequence of SEQ ID NO:39.

[0357] 6. PRO329

[0358] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to a high affinity immunoglobulin F_(c),receptor, wherein the polypeptide is designated in the presentapplication as “PRO329”.

[0359] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO329 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO329polypeptide having amino acid residues 1 to 359 of FIG. 20 (SEQ IDNO:45), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. The isolated nucleic acid sequence maycomprise the cDNA insert of the DNA40594-1233 vector deposited on Feb.5, 1998 as ATCC 209617 which includes the nucleotide sequence encodingPRO329.

[0360] In another embodiment, the invention provides isolated PRO329polypeptide. In particular, the invention provides isolated nativesequence PRO329 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 359 of FIG. 20 (SEQ ID NO:45).Optionally, the PRO329 polypeptide is obtained or is obtainable byexpressing the polypeptide encoded by the cDNA insert of theDNA40594-1233 vector deposited on Feb. 5, 1998 as ATCC 209617.

[0361] 7. PRO362

[0362] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to A33 antigen and HCAR membrane-boundprotein, wherein the polypeptide is designated in the presentapplication as “PRO362”.

[0363] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO362 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO362polypeptide having amino acid residues 1 to 321 of FIG. 22 (SEQ IDNO:52), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO362 polypeptide having aminoacid residues 1 to X of FIG. 22 (SEQ ID NO:52) where X is any amino acidfrom amino acid 271 to 280, or is complementary to such encoding nucleicacid sequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions. The isolated nucleicacid sequence may comprise the cDNA insert of the DNA45416-1251 vectordeposited on Feb. 5, 1998 as ATCC 209620 which includes the nucleotidesequence encoding PRO362.

[0364] In another embodiment, the invention provides isolated PRO362polypeptide. In particular, the invention provides isolated nativesequence PRO362 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 321 of FIG. 22 (SEQ ID NO:52). Anadditional embodiment of the present invention is directed to anisolated extracellular domain of a PRO362 polypeptide comprising aminoacids 1 to X of the amino acid sequence shown in FIG. 22 (SEQ ID NO:52),wherein X is any amino acid from amino acid 271 to 280. Optionally, thePRO362 polypeptide is obtained or is obtainable by expressing thepolypeptide encoded by the cDNA insert of the DNA45416-1251 vectordeposited on Feb. 5, 1998 as ATCC 209620.

[0365] 8. PRO363

[0366] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to the cell surface receptor protein HCAR,wherein the polypeptide is designated in the present application as“PRO363”.

[0367] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO363 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO363polypeptide having amino acid residues 1 to 373 of FIG. 24 (SEQ IDNO:59), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding a PRO363 extracellular domainpolypeptide having amino acid residues 1 to X of FIG. 24 (SEQ ID NO:59)where X is any amino acid from amino acid 216 to amino acid 225, or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA45419-1252 vector deposited on Feb. 5, 1998 asATCC 209616 which includes the nucleotide sequence encoding PRO363.

[0368] In another embodiment, the invention provides isolated PRO363polypeptide. In particular, the invention provides isolated nativesequence PRO363 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 373 of FIG. 24 (SEQ ID NO:59). Anadditional embodiment of the present invention is directed to anisolated extracellular domain of a PRO363 polypeptide, wherein thatextracellular domain may comprise amino acids 1 to X of the sequenceshown in FIG. 24 (SEQ ID NO:59), where X is any amino acid from aminoacid 216 to 225. Optionally, the PRO363 polypeptide is obtained or isobtainable by expressing the polypeptide encoded by the cDNA insert ofthe DNA45419-1252 vector deposited on Feb. 5, 1998 as ATCC 209616.

[0369] 9. PRO868

[0370] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to tumor necrosis factor receptor, whereinthe polypeptide is designated in the present application as “PRO868”.

[0371] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO868 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO868polypeptide having amino acid residues 1 to 655 of FIG. 26 (SEQ IDNO:64), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO868 polypeptide having aminoacid residues 1 to X of FIG. 26 (SEQ ID NO:64), where X is any aminoacid from amino acid 343 to 352 of the sequence shown in FIG. 26 (SEQ IDNO:64), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In yet another aspect, the isolatednucleic acid comprises DNA encoding the PRO868 polypeptide having aminoacid residues X to 655 of FIG. 26 (SEQ ID NO:64), where X is any aminoacid from amino acid 371 to 380 of the sequence shown in FIG. 26 (SEQ IDNO:64), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. The isolated nucleic acid sequence maycomprise the cDNA insert of the DNA52594-1270 vector deposited on Mar.17, 1998 as ATCC 209679 which includes the nucleotide sequence encodingPRO868.

[0372] In another embodiment, the invention provides isolated PRO868polypeptide. In particular, the invention provides isolated nativesequence PRO868 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 655 of FIG. 26 (SEQ ID NO:64). Inanother aspect, the isolated PRO868 polypeptide comprises amino acidresidues 1 to X of FIG. 26 (SEQ ID NO:64), where X is any amino acidfrom amino acid 343 to 352 of the sequence shown in FIG. 26 (SEQ IDNO:64). In yet another aspect, the PRO868 polypeptide comprises aminoacid residues X to 655 of FIG. 26 (SEQ ID NO:64), where X is any aminoacid from amino acid 371 to 380 of the sequence shown in FIG. 26 (SEQ IDNO:64). Optionally, the PRO868 polypeptide is obtained or is obtainableby expressing the polypeptide encoded by the cDNA insert of theDNA52594-1270 vector deposited on Mar. 17, 1998 as ATCC 209679.

[0373] 10. PRO382

[0374] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to serine proteases, wherein the polypeptideis designated in the present application as “PRO382”.

[0375] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO382 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO382polypeptide having amino acid residues 1 to 453 of FIG. 28 (SEQ IDNO:69), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. The isolated nucleic acid sequence maycomprise the cDNA insert of the DNA45234-1277 vector deposited on Mar.5, 1998 as ATCC 209654 which includes the nucleotide sequence encodingPRO382.

[0376] In another embodiment, the invention provides isolated PRO382polypeptide. In particular, the invention provides isolated nativesequence PRO382 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 453 of FIG. 28 (SEQ ID NO:69). Anadditional embodiment of the present invention is directed to anisolated extracellular domain of a PRO382 polypeptide, with or withoutthe signal peptide. Optionally, the PRO382 polypeptide is obtained or isobtainable by expressing the polypeptide encoded by the cDNA insert ofthe DNA45234-1277 vector deposited on Mar. 5, 1998 as ATCC 209654.

[0377] 11. PRO545

[0378] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to meltrin, wherein the polypeptide isdesignated in the present application as “PRO545”.

[0379] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO545 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO545polypeptide having amino acid residues 1 to 735 of FIG. 30 (SEQ IDNO:74), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. The isolated nucleic acid sequence maycomprise the cDNA insert of the vector deposited on Mar. 5, 1998 as ATCC209655 which includes the nucleotide sequence encoding PRO545.

[0380] In another embodiment, the invention provides isolated PRO545polypeptide. In particular, the invention provides isolated nativesequence PRO545 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 735 of FIG. 30 (SEQ ID NO:74). Anadditional embodiment of the present invention is directed to anisolated extracellular domain of a PRO545 polypeptide. Optionally, thePRO545 polypeptide is obtained or is obtainable by expressing thepolypeptide encoded by the cDNA insert of the vector deposited on Mar.5, 1998 as ATCC 209655.

[0381] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA13217 comprising thenucleotide sequence of SEQ ID NO:75 (FIG. 31).

[0382] 12. PRO617

[0383] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to CD24, wherein the polypeptide isdesignated in the present application as “PRO617”.

[0384] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO617 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO617polypeptide having amino acid residues 1 to 67 of FIG. 33 (SEQ IDNO:85), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. The isolated nucleic acid sequence maycomprise the cDNA insert of the DNA48309-1280 vector deposited on Mar.5, 1998 as ATCC 209656 which includes the nucleotide sequence encodingPRO617.

[0385] In another embodiment, the invention provides isolated PRO617polypeptide. In particular, the invention provides isolated nativesequence PRO617 polypeptide, which in one embodiment, inchldes an aminoacid sequence comprising residues 1 to 67 of FIG. 33 (SEQ ID NO:85).Optionally, the PRO617 polypeptide is obtained or is obtainable byexpressing the polypeptide encoded by the cDNA insert of theDNA48309-1280 vector deposited on Mar. 5, 1998 as ATCC 209656.

[0386] 13. PRO700

[0387] Applicants have identified a cDNA clone that encodes a novelpolypeptide having sequence similarity to protein disulfide isomerase,wherein the polypeptide is designated in the present application as“PRO700”.

[0388] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO700 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO700polypeptide having amino acid residues 1 to 432 of FIG. 35 (SEQ IDNO:90), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO700 polypeptide having aminoacid residues from about 34 to 432 of FIG. 35 (SEQ ID NO:90), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the vector deposited on Mar. 31, 1998 as ATCC 209721which includes the nucleotide sequence encoding PRO700.

[0389] In another embodiment, the invention provides isolated PRO700polypeptide. In particular, the invention provides isolated nativesequence PRO700 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 432 of FIG. 35 (SEQ ID NO:90). Inanother embodiment, the invention provides an isolated PRO700polypeptide absent the signal sequence, which includes an amino acidsequence comprising residues from about 34 to 432 of FIG. 35 (SEQ IDNO:90). Optionally, the PRO700 polypeptide is obtained or is obtainableby expressing the polypeptide encoded by the cDNA insert of the vectordeposited on Mar. 31, 1998 as ATCC 209721.

[0390] 14. PRO702

[0391] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to conglutinin, wherein the polypeptide isdesignated in the present application as “PRO702”.

[0392] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO702 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO702polypeptide having amino acid residues 1 to 277 of FIG. 37 (SEQ IDNO:97), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO702 polypeptide having aminoacid residues 26 to 277 of FIG. 37 (SEQ ID NO:97), or is complementaryto such encoding nucleic acid sequence, and remains stably bound to itunder at least moderate, and optionally, under high stringencyconditions. The isolated nucleic acid sequence may comprise the cDNAinsert of the DNA50980-1286 vector deposited on Mar. 31, 1998 as ATCC209717 which includes the nucleotide sequence encoding PRO702.

[0393] In another embodiment, the invention provides isolated PRO702polypeptide. In particular, the invention provides isolated nativesequence PRO702 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 277 of FIG. 37 (SEQ ID NO:97). Anadditional embodiment of the present invention is directed to anisolated PRO702 polypeptide comprising amino acid residues 26 to 277 ofFIG. 37 (SEQ ID NO:97). Optionally, the PRO702 polypeptide is obtainedor is obtainable by expressing the polypeptide encoded by the cDNAinsert of the DNA50980-1286 vector deposited on Mar. 31, 1998 as ATCC209717.

[0394] 15. PRO703

[0395] Applicants have identified a cDNA clone that encodes a novelpolypeptide having sequence similarity to VLCAS, wherein the polypeptideis designated in the present application as “PRO703”.

[0396] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO703 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO703polypeptide having amino acid residues 1 to 730 of FIG. 39 (SEQ ID NO:102), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO703 polypeptide having aminoacid residues from about 43 to 730 of FIG. 39 (SEQ ID NO: 102), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA50913-1287 vector deposited on Mar. 31, 1998as ATCC 209716 which includes the nucleotide sequence encoding PRO703.

[0397] In another embodiment, the invention provides isolated PRO703polypeptide. In particular, the invention provides isolated nativesequence PRO703 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 730 of FIG. 39 (SEQ ID NO: 102).In another embodiment, the invention provides an isolated PRO703polypeptide absent the signal sequence, which includes an amino acidsequence comprising residues from about 43 to 730 of FIG. 30 (SEQ ID NO:102). Optionally, the PRO730 polypeptide is obtained or is obtainable byexpressing the polypeptide encoded by the cDNA insert of theDNA50913-1287 vector deposited on Mar. 31, 1998 as ATCC 209716.

[0398] 16. PRO705

[0399] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to K-glypican, wherein the polypeptide isdesignated in the present application as “PRO705”.

[0400] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO705 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO705polypeptide having amino acid residues 1 to 555 of FIG. 41 (SEQ ID NO:109), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO705 polypeptide having aminoacid residues about 24 to 555 of FIG. 41 (SEQ ID NO: 109), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA50914-1289 vector deposited on Mar. 31, 1998as ATCC 209722 which includes the nucleotide sequence encoding PRO705.

[0401] In another embodiment, the invention provides isolated PRO705polypeptide. In particular, the invention provides isolated nativesequence PRO705 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 555 of FIG. 41 (SEQ ID NO: 109).An additional embodiment of the present invention is directed to anisolated PRO705 polypeptide comprising amino acid residues about 24 to555 of FIG. 41 (SEQ ID NO: 109). Optionally, the PRO705 polypeptide isobtained or is obtainable by expressing the polypeptide encoded by thecDNA insert of the DNA50914-1289 vector deposited on Mar. 31, 1998 asATCC 209722.

[0402] 17. PRO708

[0403] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to the aryl sulfatases, wherein thepolypeptide is designated in the present application as “PRO708”.

[0404] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO708 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO708polypeptide having amino acid residues 1 to 515 of FIG. 43 (SEQ IDNO:114), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. The isolated nucleic acid sequence maycomprise the cDNA insert of the DNA48296-1292 vector deposited on Mar.11, 1998 as ATCC 209668 which includes the nucleotide sequence encodingPRO708.

[0405] In another embodiment, the invention provides isolated PRO708polypeptide. In particular, the invention provides isolated nativesequence PRO708 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 515 of FIG. 43 (SEQ ID NO:114).Another embodiment is directed to a PRO708 polypeptide comprisingresidues 38-515 of the amino acid sequence shown in FIG. 43 (SEQ IDNO:114). Optionally, the PRO708 polypeptide is obtained or is obtainableby expressing the polypeptide encoded by the cDNA insert of theDNA48296-1292 vector deposited on Mar. 11, 1998 as ATCC 209668.

[0406] 18. PRO320

[0407] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to fibulin, wherein the polypeptide isdesignated in the present application as “PRO320”.

[0408] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO320 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO320polypeptide having amino acid residues 1 to 338 of FIG. 45 (SEQ ID NO:119), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. The isolated nucleic acid sequence maycomprise the cDNA insert of the vector deposited on Mar. 11, 1998 asATCC 209670 which includes the nucleotide sequence encoding PRO320.

[0409] In another embodiment, the invention provides isolated PRO320polypeptide. In particular, the invention provides isolated nativesequence PRO320 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 338 of FIG. 45 (SEQ ID NO:119).Optionally, the PRO320 polypeptide is obtained or is obtainable byexpressing the polypeptide encoded by the cDNA insert of the vectordeposited on Mar. 11, 1998 as ATCC 209670.

[0410] 19. PRO324

[0411] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to oxidoreductases, wherein the polypeptideis designated in the present application as “PRO324”.

[0412] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO324 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO324polypeptide having amino acid residues 1 to 289 of FIG. 47 (SEQ ID NO:124), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO324 polypeptide having amino acidresidues 1 or about 32 to X of FIG. 47 (SEQ ID NO:124), where X is anyamino acid from 131 to 140, or is complementary to such encoding nucleicacid sequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions. The isolated nucleicacid sequence may comprise the cDNA insert of the DNA36343-1310 vectordeposited on Mar. 30, 1998 as ATCC 209718 which includes the nucleotidesequence encoding PRO324.

[0413] In another embodiment, the invention provides isolated PRO324polypeptide. In particular, the invention provides isolated nativesequence PRO324 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 289 of FIG. 47 (SEQ ID NO:124).The invention also provides isolated PRO324 polypeptide comprisingresidues 1 or about 32 to X of FIG. 47 (SEQ ID NO:124), wherein X is anyamino acid from about 131-140. Optionally, the PRO324 polypeptide isobtained or is obtainable by expressing the polypeptide encoded by thecDNA insert of the DNA36343-1310 vector deposited on Mar. 30, 1998 asATCC 209718.

[0414] 20. PRO351

[0415] Applicants have identified a cDNA clone that encodes a novelpolypeptide having sequence similarity to prostasin, wherein thepolypeptide is designated in the present application as “PRO351”.

[0416] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO351 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO351polypeptide having amino acid residues 1 to 571 of FIG. 49 (SEQ IDNO:132), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO351 polypeptide having aminoacid residues about 16 to 571 of FIG. 49 (SEQ ID NO:132), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA40571-1315 vector deposited on Apr. 21, 1998as ATCC 209784 which includes the nucleotide sequence encoding PRO351.

[0417] In another embodiment, the invention provides isolated PRO351polypeptide. In particular, the invention provides isolated nativesequence PRO351 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 571 of FIG. 49 (SEQ ID NO:132).In another embodiment, the invention provides an isolated PRO351polypeptide absent the signal sequence, which includes an amino acidsequence comprising residues from about 16 to 571 of FIG. 49 (SEQ IDNO:132). Optionally, the PRO351 polypeptide is obtained or is obtainableby expressing the polypeptide encoded by the cDNA insert of theDNA40571-1315 vector deposited on Apr. 21, 1998 as ATCC 209784.

[0418] 21. PRO352

[0419] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to butyrophilin, wherein the polypeptide isdesignated in the present application as “PRO352”.

[0420] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO352 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO352polypeptide having amino acid residues 1 to 316 of FIG. 51 (SEQ IDNO:137), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO352 polypeptide having amino acidresidues of about 29 to 316 of FIG. 51 (SEQ ID NO:137), or 1 or about 29to X of FIG. 51, where X is any amino acid from 246 to 255, or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA41386-1316 vector deposited on Mar. 26, 1998as ATCC 209703 which includes the nucleotide sequence encoding PRO352.

[0421] In another embodiment, the invention provides isolated PRO352polypeptide. In particular, the invention provides isolated nativesequence PRO352 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 316 of FIG. 51 (SEQ ID NO:137).In other embodiments, the invention provides isolated PRO352 polypeptidecomprising residues about 29 to 316 of FIG. 51 (SEQ ID NO:137) and 1 orabout 29 to X of FIG. 51 (SEQ ID NO:137), wherein X is any amino acidfrom 246 to 255. Optionally, the PRO352 polypeptide is obtained or isobtainable by expressing the polypeptide encoded by the cDNA insert ofthe DNA41386-1316 vector deposited on Mar. 26, 1998 as ATCC 209703.

[0422] 22. PRO381

[0423] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to immunophilin proteins, wherein thepolypeptide is designated in the present application as “PRO381”.

[0424] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO381 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO381polypeptide having amino acid residues 1 to 211 of FIG. 53 (SEQ IDNO:145), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO381 polypeptide having aminoacid residues about 21 to 211 of FIG. 53 (SEQ ID NO:145), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA44194-1317 vector deposited on Apr. 28, 1998as ATCC 209808 which includes the nucleotide sequence encoding PRO381.

[0425] In another embodiment, the invention provides isolated PRO381polypeptide. In particular, the invention provides isolated nativesequence PRO381 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 211 of FIG. 53 (SEQ ID NO:145).Another embodiment is directed to a PRO381 plypeptide comprising aminoacids about 21 to 211 of FIG. 53 (SEQ ID NO:145). Optionally, the PRO381polypeptide is obtained or is obtainable by expressing the polypeptideencoded by the cDNA insert of the DNA44194-1317 vector deposited on Apr.28, 1998 as ATCC 209808.

[0426] 23. PRO386

[0427] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to the beta-2 subunit of a sodium channel,wherein the polypeptide is designated in the present application as“PRO386”.

[0428] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO386 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO386polypeptide having amino acid residues 1 to 215 of FIG. 55 (SEQ IDNO:150), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO386 polypeptide having aminoacid residues about 21 to 215 of FIG. 55 (SEQ ID NO:150) or 1 or about21 to X, where X is any amino acid from 156 to 165 of FIG. 55 (SEQ IDNO: 150), or is complementary to such encoding nucleic acid sequence,and remains stably bound to it under at least moderate, and optionally,under high stringency conditions. The isolated nucleic acid sequence maycomprise the cDNA insert of the DNA45415-1318 vector deposited on Apr.28, 1998 as ATCC 209810 which includes the nucleotide sequence encodingPRO386.

[0429] In another embodiment, the invention provides isolated PRO386polypeptide. In particular, the invention provides isolated nativesequence PRO386 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 215 of FIG. 55 (SEQ ID NO:150).Other embodiments of the present invention are directed to PRO386polypeptides comprising amino acids about 21 to 215 of FIG. 55 (SEQ IDNO:150) and 1 or about 21 to X of FIG. 55 (SEQ ID NO:150), wherein X isany amino acid from 156 to 165 of FIG. 55 (SEQ ID NO:150). Optionally,the PRO386 polypeptide is obtained or is obtainable by expressing thepolypeptide encoded by the cDNA insert of the DNA45415-1318 vectordeposited on Apr. 28, 1998 as ATCC 209810.

[0430] In another embodiment, the invention provides an expressedsequence tag (EST) comprising the nucleotide sequence of SEQ ID NO:151which corrsponds to an EST designated herein as DNA23350.

[0431] In another embodiment, the invention provides an expressedsequence tag (EST) comprising the nucleotide sequence of SEQ ID NO:152which corrsponds to an EST designated herein as DNA23536.

[0432] 24. PRO540

[0433] Applicants have identified a cDNA clone that encodes a novelpolypeptide having sequence similarity to LCAT, wherein the polypeptideis designated in the present application as “PRO540”.

[0434] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO540 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO540polypeptide having amino acid residues 1 to 412 of FIG. 59 (SEQ IDNO:157), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO540 polypeptide having aminoacid residues about 29 to 412 of FIG. 59 (SEQ ID NO: 157), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA44189-1322 vector deposited on Mar. 26, 1998as ATCC 209699 which includes the nucleotide sequence encoding PRO540.

[0435] In another embodiment, the invention provides isolated PRO540polypeptide. In particular, the invention provides isolated nativesequence PRO540 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 412 of FIG. 59 (SEQ ID NO:157).The invention also provides isolated PRO540 polypeptide, which in oneembodiment, includes an amino acid sequence comprising residues about 29to 412 of FIG. 59 (SEQ ID NO:157). Optionally, the PRO540 polypeptide isobtained or is obtainable by expressing the polypeptide encoded by thecDNA insert of the DNA44189-1322 vector deposited on Mar. 26, 1998 asATCC 209699.

[0436] 25. PRO615

[0437] Applicants have identified a cDNA clone that encodes a novelpolypeptide having sequence similarity to synaptogyrin, wherein thepolypeptide is designated in the present application as “PRO615”.

[0438] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO615 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO615polypeptide having amino acid residues 1 to 224 of FIG. 61 (SEQ IDNO:162), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO615 polypeptide having aminoacid residues X to 224 of FIG. 61 (SEQ ID NO:162), where X is any aminoacid from 157 to 166, or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate, andoptionally, under high stringency conditions. The isolated nucleic acidsequence may comprise the cDNA insert of the DNA48304-1323 vectordeposited on Apr. 28, 1998 as ATCC 209811 which includes the nucleotidesequence encoding PRO615.

[0439] In another embodiment, the invention provides isolated PRO615polypeptide. In particular, the invention provides isolated nativesequence PRO615 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 224 of FIG. 61 (SEQ ID NO:162).An additional embodiment of the present invention is directed to anisolated extracellular domain of a PRO615 polypeptide which comprisesamino acid residues X to 224 of FIG. 61 (SEQ ID NO:162), where X is anyamino acid from 157 to 166 of FIG. 61 (SEQ ID NO:162). Optionally, thePRO615 polypeptide is obtained or is obtainable by expressing thepolypeptide encoded by the cDNA insert of the DNA48304-1323 vectordeposited on Apr. 28, 1998 as ATCC 209811.

[0440] 26. PRO618

[0441] Applicants have identified a cDNA clone that encodes a novelpolypeptide having sequence similarity to enteropeptidase, wherein thepolypeptide is designated in the present application as “PRO618”.

[0442] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO618 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO618polypeptide having amino acid residues 1 to 802 of FIG. 63 (SEQ IDNO:169), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding an isolated extracellular domain ofa PRO618 polypeptide having amino acid residues X to 802 of FIG. 63 (SEQID NO:169), where X is any amino acid from 63 to 72 of FIG. 63 (SEQ IDNO:169), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. The isolated nucleic acid sequence maycomprise the cDNA insert of the DNA49152-1324 vector deposited on Apr.28, 1998 as ATCC 209813 which includes the nucleotide sequence encodingPRO618.

[0443] In another embodiment, the invention provides isolated PRO618polypeptide. In particular, the invention provides isolated nativesequence PRO618 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 802 of FIG. 63 (SEQ ID NO:169).An additional embodiment of the present invention is directed to anisolated extracellular domain of a PRO618 polypeptide comprising aminoacid X to 802 where X is any amino acid from 63 to 72 of FIG. 63 (SEQ IDNO:169). Optionally, the PRO618 polypeptide is obtained or is obtainableby expressing the polypeptide encoded by the cDNA insert of theDNA49152-1324 vector deposited on Apr. 28, 1998 as ATCC 209813.

[0444] In another embodiment, the invention provides an expressedsequence tag (EST) comprising the nucleotide sequence of SEQ ID NO: 170,designated herein as DNA35597 (see FIG. 64).

[0445] 27. PRO719

[0446] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to lipoprotein lipase H, wherein thepolypeptide is designated in the present application as “PRO719”.

[0447] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO719 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO719polypeptide having amino acid residues 1 to 354 of FIG. 66 (SEQ ID NO:178), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO719 polypeptide having aminoacid residues about 17 to 354 of FIG. 66 (SEQ ID NO: 178), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA49646-1327 vector deposited on Mar. 26, 1998as ATCC 209705 which includes the nucleotide sequence encoding PRO719.

[0448] In another embodiment, the invention provides isolated PRO719polypeptide. In particular, the invention provides isolated nativesequence PRO719 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 354 of FIG. 66 (SEQ ID NO: 178).In another embodiment, the invention provides isolated PRO719polypeptide which comprises residues about 17 to 354 of FIG. 66 (SEQ IDNO:178). Optionally, the PRO719 polypeptide is obtained or is obtainableby expressing the polypeptide encoded by the cDNA insert of theDNA49646-1327 vector deposited on Mar. 26, 1998 as ATCC 209705.

[0449] 28. PRO724

[0450] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to the LDL receptor, wherein the polypeptideis designated in the present application as “PRO724”.

[0451] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO724 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO724polypeptide having amino acid residues 1 to 713 of FIG. 68 (SEQ IDNO:183), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding a soluble PRO724 polypeptide havingamino acid residues 1 to X of FIG. 68 (SEQ ID NO:183) where X is anyamino acid from amino acid 437 to 446, or is complementary to suchencoding nucleic acid sequence, and remains stably bound to it under atleast moderate, and optionally, under high stringency conditions. Theabove two polypeptides may either possess or not possess the signalpeptide. The isolated nucleic acid sequence may comprise the cDNA insertof the DNA49631-1328 vector deposited on Apr. 28, 1998 as ATCC 209806which includes the nucleotide sequence encoding PRO724.

[0452] In another embodiment, the invention provides isolated PRO724polypeptide. In particular, the invention provides isolated nativesequence PRO724 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 713 of FIG. 68 (SEQ ID NO:183).In another embodiment, the invention provides isolated soluble PRO724polypeptide. In particular, the invention provides isolated solublePRO724 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 to X of FIG. 68 (SEQ ID NO: 183), where Xis any amino acid from 437 to 446 of the sequence shown in FIG. 68 (SEQID NO:183). Optionally, the PRO724 polypeptide is obtained or isobtainable by expressing the polypeptide encoded by the cDNA insert ofthe DNA49631-1328 vector deposited on Apr. 28, 1998 as ATCC 209806.

[0453] 29. PRO772

[0454] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to A4 protein, wherein the polypeptide isdesignated in the present application as “PRO772”.

[0455] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO772 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO772polypeptide having amino acid residues 1 to 152 of FIG. 70 (SEQ IDNO:190), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO772 polypeptide having amino acidresidues 1 to X of FIG. 70 (SEQ ID NO:190), where X is any amino acidfrom 21 to 30 of FIG. 70 (SEQ ID NO:190), or is complementary to suchencoding nucleic acid sequence, and remains stably bound to it under atleast moderate, and optionally, under high stringency conditions. Theisolated nucleic acid sequence may comprise the cDNA insert of theDNA49645-1347 vector deposited on Apr. 28, 1998 as ATCC 209809 whichincludes the nucleotide sequence encoding PRO772.

[0456] In another embodiment, the invention provides isolated PRO772polypeptide. In particular, the invention provides isolated nativesequence PRO772 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 152 of FIG. 70 (SEQ ID NO:190).Additional embodiments of the present invention are directed to PRO772polypeptides comprising amino acids 1 to X of FIG. 70 (SEQ ID NO:190),where X is any amino acid from 21 to 30 of FIG. 70 (SEQ ID NO:190).Optionally, the PRO772 polypeptide is obtained or is obtainable byexpressing the polypeptide encoded by the cDNA insert of theDNA49645-1347 vector deposited on Apr. 28, 1998 as ATCC 209809.

[0457] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA43509 comprising thenucleotide sequence of SEQ ID NO:191 (FIG. 71).

[0458] 30. PRO852

[0459] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to various protease enzymes, wherein thepolypeptide is designated in the present application as “PRO852”.

[0460] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO852 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO852polypeptide having amino acid residues 1 to 518 of FIG. 73 (SEQ IDNO:196), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO852 polypeptide having amino acidresidues about 21 to 518 of FIG. 73 (SEQ ID NO: 196) or 1 or about 21 toX of FIG. 73 (SEQ ID NO:196) where X is any amino acid from amino acid461 to amino acid 470 of FIG. 73 (SEQ ID NO:196), or is complementary tosuch encoding nucleic acid sequence, and remains stably bound to itunder at least moderate, and optionally, under high stringencyconditions. The isolated nucleic acid sequence may comprise the cDNAinsert of the DNA45493-1349 vector deposited on Apr. 28, 1998 as ATCC209805 which includes the nucleotide sequence encoding PRO852.

[0461] In another embodiment, the invention provides isolated PRO852polypeptide. In particular, the invention provides isolated nativesequence PRO852 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 518 of FIG. 73 (SEQ ID NO:196).In other embodiments, the PRO852 comprises amino acids about 21 to aminoacid 518 of FIG. 73 (SEQ ID NO:196) or amino acids 1 or about 21 to X ofFIG. 73 (SEQ ID NO:196), where X is any amino acid from amino acid 461to amino acid 470 of FIG. 73 (SEQ ID NO:196). Optionally, the PRO852polypeptide is obtained or is obtainable by expressing the polypeptideencoded by the cDNA insert of the DNA45493-1349 vector deposited on Apr.28, 1998 as ATCC 209805.

[0462] 31. PRO853

[0463] Applicants have identified a cDNA clone that encodes a novelpolypeptide having sequence similarity to reductase, wherein thepolypeptide is designated in the present application as “PRO853”.

[0464] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO853 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO853polypeptide having amino acid residues 1 to 377 of FIG. 75 (SEQ IDNO:206), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO853 polypeptide having aminoacid residues about 17 to 377 of FIG. 75 (SEQ ID NO:206), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA48227-1350 vector deposited on Apr. 28, 1998as ATCC 209812 which includes the nucleotide sequence encoding PRO853.

[0465] In another embodiment, the invention provides isolated PRO853polypeptide. In particular, the invention provides isolated nativesequence PRO853 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 377 of FIG. 75 (SEQ ID NO:206).In another embodiment, the invention provides an isolated PRO853polypeptide absent the signal sequence, which includes an amino acidsequence comprising residues from about 17 to 377 of FIG. 75 (SEQ IDNO:206). Optionally, the PRO853 polypeptide is obtained or is obtainableby expressing the polypeptide encoded by the cDNA insert of theDNA48227-1350 vector deposited on Apr. 28, 1998 as ATCC 209812.

[0466] 32. PRO860

[0467] Applicants have identified a cDNA clone that encodes a novelpolypeptide having sequence similarity to neurofascin, wherein thepolypeptide is designated in the present application as “PRO860”.

[0468] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO860 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO860polypeptide having amino acid residues 1 to 985 of FIG. 77 (SEQ IDNO:211), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO860 polypeptide having aminoacid residues 1 to X of FIG. 77 (SEQ ID NO:211), where X is any aminoacid from 443452 of FIG. 77 (SEQ ID NO:211), or is complementary to suchencoding nucleic acid sequence, and remains stably bound to it under atleast moderate, and optionally, under high stringency conditions. Theisolated nucleic acid sequence may comprise the cDNA insert of theDNA41404-1352 vector deposited on May 6, 1998 as ATCC 209844 whichincludes the nucleotide sequence encoding PRO860.

[0469] In another embodiment, the invention provides isolated PRO860polypeptide. In particular, the invention provides isolated nativesequence PRO860 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 985 of FIG. 77 (SEQ ID NO:211).In another embodiment, the invention provides an isolated PRO860polypeptide which includes an amino acid sequence comprising residues 1to X of FIG. 77 (SEQ ID NO:211), where X is any amino acid residue from443 to 452 of FIG. 77 (SEQ ID NO:211). Optionally, the PRO860polypeptide is obtained or is obtainable by expressing the polypeptideencoded by the cDNA insert of the DNA41404-1352 vector deposited on May6, 1998 as ATCC 209844.

[0470] 33. PRO846

[0471] Applicants have identified a cDNA clone that encodes a novelpolypeptide having sequence similarity to CMRF35, wherein thepolypeptide is designated in the present application as “PRO846”.

[0472] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO846 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO846polypeptide having amino acid residues 1 to 332 of FIG. 79 (SEQ IDNO:216), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO846 polypeptide having amino acidresidues about 18 to 332 of FIG. 79 (SEQ ID NO:216) or 1 or about 18 toX of SEQ ID NO:216, where X is any amino acid from 243 to 252 of FIG. 79(SEQ ID NO:216), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate, andoptionally, under high stringency conditions. The isolated nucleic acidsequence may comprise the cDNA insert of the DNA44196-1353 vectordeposited on May 6, 1998 as ATCC 209847 which includes the nucleotidesequence encoding PRO846.

[0473] In another embodiment, the invention provides isolated PRO846polypeptide. In particular, the invention provides isolated nativesequence PRO846 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 332 of FIG. 79 (SEQ ID NO:216).In other embodiments, the invention provides an isolated PRO846polypeptide absent the signal sequence, which includes an amino acidsequence comprising residues from about 18 to 332 of FIG. 79 (SEQ IDNO:216). Additional embodiments of the present invention are directed toan isolated PRO846 polypeptide comprising amino acid 1 or about 18 to Xof FIG. 79 (SEQ ID NO:216), where X is any amino acid from 243 to 252 ofFIG. 79 (SEQ ID NO:216). Optionally, the PRO846 polypeptide is obtainedor is obtainable by expressing the polypeptide encoded by the cDNAinsert of the DNA44196-1353 vector deposited on May 6, 1998 as ATCC209847.

[0474] 34. PRO862

[0475] Applicants have identified a cDNA clone that encodes a novelpolypeptide having sequence similarity to lysozyme, wherein thepolypeptide is designated in the present application as “PRO862”.

[0476] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO862 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO862polypeptide having amino acid residues 1 to 146 of FIG. 81 (SEQ IDNO:221), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO862 polypeptide having aminoacid residues about 19 to 146 of FIG. 81 (SEQ ID NO:221), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA52187-1354 vector deposited on May 6, 1998 asATCC 209845 which includes the nucleotide sequence encoding PRO862.

[0477] In another embodiment, the invention provides isolated PRO862polypeptide. In particular, the invention provides isolated nativesequence PRO862 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 146 of FIG. 81 (SEQ ID NO:221).In another embodiment, the invention provides an isolated PRO862polypeptide absent the signal sequence, which includes an amino acidsequence comprising residues from about 19 to 146 of FIG. 81 (SEQ IDNO:221). Optionally, the PRO862 polypeptide is obtained or is obtainableby expressing the polypeptide encoded by the cDNA insert of theDNA52187-1354 vector deposited on May 6, 1998 as ATCC 209845.

[0478] 35. PRO864

[0479] Applicants have identified a cDNA clone that encodes a novelpolypeptide having sequence similarity to Wnt-4, wherein the polypeptideis designated in the present application as “PRO864”.

[0480] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO864 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO864polypeptide having amino acid residues 1 to 351 of FIG. 83 (SEQ IDNO:226), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO864 polypeptide having aminoacid residues about 23 to 351 of FIG. 83 (SEQ ID NO:226), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA48328-1355 vector deposited on May 6, 1998 asATCC 209843 which includes the nucleotide sequence encoding PRO864.

[0481] In another embodiment, the invention provides isolated PRO864polypeptide. In particular, the invention provides isolated nativesequence PRO864 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 351 of FIG. 83 (SEQ ID NO:226).In another embodiment, the invention provides an isolated PRO864polypeptide absent the signal sequence, which includes an amino acidsequence comprising residues from about 23 to 351 of FIG. 83 (SEQ IDNO:226). Optionally, the PRO864 polypeptide is obtained or is obtainableby expressing the polypeptide encoded by the cDNA insert of theDNA48328-1355 vector deposited on May 6, 1998 as ATCC 209843.

[0482] 36. PRO792

[0483] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to CD23, wherein the polypeptide isdesignated in the present application as “PRO792”.

[0484] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO792 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO792polypeptide having amino acid residues 1 to 293 of FIG. 85 (SEQ IDNO:231), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO792 polypeptide having aminoacid residues X to 293 of FIG. 85 (SEQ ID NO:231) where X is any aminoacid from 50 to 59 of FIG. 85 (SEQ ID NO:231), or is complementary tosuch encoding nucleic acid sequence, and remains stably bound to itunder at least moderate, and optionally, under high stringencyconditions. The isolated nucleic acid sequence may comprise the cDNAinsert of the DNA56352-1358 vector deposited on May 6, 1998 as ATCC209846 which includes the nucleotide sequence encoding PRO792.

[0485] In another embodiment, the invention provides isolated PRO792polypeptide. In particular, the invention provides isolated nativesequence PRO792 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 293 of FIG. 85 (SEQ ID NO:231).An additional embodiment of the present invention is directed to PRO792polypeptide comprising amino acids X to 293 of FIG. 85 (SEQ ID NO:231),where X is any amino acid from 50 to 59 of FIG. 85 (SEQ ID NO:231).Optionally, the PRO792 polypeptide is obtained or is obtainable byexpressing the polypeptide encoded by the cDNA insert of theDNA56352-1358 vector deposited on May 6, 1998 as ATCC 209846.

[0486] 37. PRO866

[0487] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to mindin and spondin proteins, wherein thepolypeptide is designated in the present application as “PRO866”.

[0488] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO866 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO866polypeptide having amino acid residues 1 to 331 of FIG. 87 (SEQ IDNO:236), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In another aspect, the isolatednucleic acid comprises DNA encoding the PRO866 polypeptide having aminoacid residues about 27 to 229 of FIG. 87 (SEQ ID NO:236), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA53971-1359 vector deposited on Apr. 7, 1998 asATCC 209750 which includes the nucleotide sequence encoding PRO866.

[0489] In another embodiment, the invention provides isolated PRO866polypeptide. In particular, the invention provides isolated nativesequence PRO866 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 331 of FIG. 87 (SEQ ID NO:236).Another embodiment of the present invention is directed to PRO866polypeptides comprising amino acids about 27 to 331 of FIG. 87 (SEQ IDNO:236). Optionally, the PRO866 polypeptide is obtained or is obtainableby expressing the polypeptide encoded by the cDNA insert of theDNA53971-1359 vector deposited on Apr. 7, 1998 as ATCC 209750.

[0490] 38. PRO871

[0491] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to CyP-60, wherein the polypeptide isdesignated in the present application as “PRO871”.

[0492] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO871 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO871polypeptide having amino acid residues 1 to 472 of FIG. 89 (SEQ IDNO:245), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO871 polypeptide having amino acidresidues about 22 to 472 of FIG. 89 (SEQ ID NO:245), or is complementaryto such encoding nucleic acid sequence, and remains stably bound to itunder at least moderate, and optionally, under high stringencyconditions. The isolated nucleic acid sequence may comprise the cDNAinsert of the DNA50919-1361 vector deposited on May 6, 1998 as ATCC209848 which includes the nucleotide sequence encoding PRO871.

[0493] In another embodiment, the invention provides isolated PRO871polypeptide. In particular, the invention provides isolated nativesequence PRO871 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 472 of FIG. 89 (SEQ ID NO:245).An additional embodiment of the present invention is directed to PRO871polypeptides comprising amino acids about 22 to 472 of FIG. 89 (SEQ IDNO:245). Optionally, the PRO871 polypeptide is obtained or is obtainableby expressing flie polypeptide encoded by the cDNA insert of theDNA50919-1361 vector deposited on May 6, 1998 as ATCC 209848.

[0494] 39. PRO873

[0495] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to carboxylesterase, wherein the polypeptideis designated in the present application as “PRO873”.

[0496] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO873 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO873polypeptide having amino acid residues 1 to 545 of FIG. 91 (SEQ IDNO:254), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO873 polypeptide having amino acidresidues about 30 to about 545 of FIG. 91 (SEQ ID NO:254), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA44179-1362 vector deposited on May 6, 1998 asATCC 209851 which includes the nucleotide sequence encoding PRO873.

[0497] In another embodiment, the invention provides isolated PRO873polypeptide. In particular, the invention provides isolated nativesequence PRO873 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 545 of FIG. 91 (SEQ ID NO:254).Additional embodiments of the present invention are directed to PRO873polypeptides comprising amino acids about 30 to about 545 of FIG. 91(SEQ ID NO:254). Optionally, the PRO873 polypeptide is obtained or isobtainable by expressing the polypeptide encoded by the cDNA insert ofthe DNA44179-1362 vector deposited on May 6, 1998 as ATCC 209851.

[0498] 40. PRO940

[0499] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to CD33 and OB binding protein-2, whereinthe polypeptide is designated in the present application as “PRO940”.

[0500] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO940 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO940polypeptide having amino acid residues 1 to 544 of FIG. 93 (SEQ IDNO:259), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO940 polypeptide having amino acidresidues about 16 to 544 of FIG. 93 (SEQ ID NO:259) or 1 or about 16 toX of FIG. 93 (SEQ ID NO:259), where X is any amino acid from 394 to 403of FIG. 93 (SEQ ID NO:259), or is complementary to such encoding nucleicacid sequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions. The isolated nucleicacid sequence may comprise the cDNA insert of the DNA54002-1367 vectordeposited on Apr. 7, 1998 as ATCC 209754 which includes the nucleotidesequence encoding PRO940.

[0501] In another embodiment, the invention provides isolated PRO940polypeptide. In particular, the invention provides isolated nativesequence PRO940 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 544 of FIG. 93 (SEQ ID NO:259).Other embodiments of the present invention are directed to PRO940polypeptides comprising amino acids about 16 to 544 of FIG. 93 (SEQ IDNO:259) or 1 or about 16 to X of FIG. 93 (SEQ ID NO:259), where X is anyamino acid from 394 to 403 of FIG. 93 (SEQ ID NO:259). Optionally, thePRO940 polypeptide is obtained or is obtainable by expressing thepolypeptide encoded by the cDNA insert of the DNA54002-1367 vectordeposited on Apr. 7, 1998 as ATCC 209754.

[0502] 41. PRO941

[0503] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to a cadherin protein, wherein thepolypeptide is designated in the present application as “PRO941”.

[0504] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO941 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO941polypeptide having amino acid residues 1 to 772 of FIG. 95 (SEQ IDNO:264), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO941 polypeptide having amino acidresidues about 22 to 772 of FIG. 95 (SEQ ID NO:264) or 1 or about 22 toX of FIG. 95 (SEQ ID NO:264), where X is any amino acid from 592 to 601of FIG. 95 (SEQ ID NO:264), or is complementary to such encoding nucleicacid sequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions. The isolated nucleicacid sequence may comprise the cDNA insert of the DNA53906-1368 vectordeposited on Apr. 7, 1998 as ATCC 209747 which includes the nucleotidesequence encoding PRO941.

[0505] In another embodiment, the invention provides isolated PRO941polypeptide. In particular, the invention provides isolated nativesequence PRO941 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 772 of FIG. 95 (SEQ ID NO:264).Additional embodiments of the present invention are directed to PRO941polypeptides which comprise amino acid about 21 to 772 of FIG. 95 (SEQID NO:264) or 1 or about 22 to X of FIG. 95 (SEQ ID NO:264), where X isany amino acid from 592 to 601 of FIG. 95 (SEQ ID NO:264). Optionally,the PRO941 polypeptide is obtained or is obtainable by expressing thepolypeptide encoded by the cDNA insert of the DNA53906-1368 vectordeposited on Apr. 7, 1998 as ATCC 209747.

[0506] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA6415 comprising thenucleotide sequence of FIG. 96 (SEQ ID NO:265).

[0507] 42. PRO944

[0508] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to Clostndium perfringens enterotoxinreceptor (CPE-R), wherein the polypeptide is designated in the presentapplication as “PRO944”.

[0509] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO944 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO944polypeptide having amino acid residues 1 to 211 of FIG. 98 (SEQ IDNO:270), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO944 polypeptide having amino acidresidues about 22 to 229 of FIG. 98 (SEQ ID NO:270) or amino acid 1 orabout 22 to X of FIG. 98 (SEQ ID NO:270) where X is any amino acid from77 to 80 of FIG. 98 (SEQ ID NO:270), or is complementary to suchencoding nucleic acid sequence, and remains stably bound to it under atleast moderate, and optionally, under high stringency conditions. Theisolated nucleic acid sequence may comprise the cDNA insert of theDNA52185-1370 vector deposited on May 14, 1998 as ATCC 209861 whichincludes the nucleotide sequence encoding PRO944.

[0510] In another embodiment, the invention provides isolated PRO944polypeptide. In particular, the invention provides isolated nativesequence PRO944 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 211 of FIG. 98 (SEQ ID NO:270).Additional embodiments of the present invention are directed to PRO944polypeptides comprising amino acids about 22 to 211 of FIG. 98 (SEQ IDNO:270) or amino acid 1 or about 22 to X of FIG. 98 (SEQ ID NO:270),where X is any amino acid from 77 to 86 of FIG. 98 (SEQ ID NO:270).Optionally, the PRO944 polypeptide is obtained or is obtainable byexpressing the polypeptide encoded by the cDNA insert of theDNA52185-1370 vector deposited on May 14, 1998 as ATCC 209861.

[0511] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA14007 comprising thenucleotide sequence of FIG. 99 (SEQ ID NO:271).

[0512] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA12733 comprising thenucleotide sequence of FIG. 100 (SEQ ID NO:272).

[0513] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA12746 comprising thenucleotide sequence of FIG. 101 (SEQ ID NO:273).

[0514] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA12834 comprising thenucleotide sequence of FIG. 102 (SEQ ID NO:274).

[0515] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA12846 comprising thenucleotide sequence of FIG. 103 (SEQ ID NO:275).

[0516] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA13104 comprising thenucleotide sequence of FIG. 104 (SEQ ID NO:276).

[0517] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA13259 comprising thenucleotide sequence of FIG. 105 (SEQ ID NO:277).

[0518] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA13959 comprising thenucleotide sequence of FIG. 106 (SEQ ID NO:278).

[0519] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA13961 comprising thenucleotide sequence of FIG. 107 (SEQ ID NO:279).

[0520] 43. PRO983

[0521] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to a vesicle associated protein, VAP-33,wherein the polypeptide is designated in the present application as“PRO983”.

[0522] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO983 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO983polypeptide having amino acid residues 1 to 243 of FIG. 109 (SEQ IDNO:284), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO983 polypeptide having amino acidresidue 1 to X of FIG. 109 (SEQ ID NO:284) where X is any amino acidfrom 219 to 228 of FIG. 109 (SEQ ID NO:284), or is complementary to suchencoding nucleic acid sequence, and remains stably bound to it under atleast moderate, and optionally, under high stringency conditions. Theisolated nucleic acid sequence may comprise the cDNA insert of theDNA53977-1371 vector deposited on May 14, 1998 as ATCC 209862 whichincludes the nucleotide sequence encoding PRO983.

[0523] In another embodiment, the invention provides isolated PRO983polypeptide. In particular, the invention provides isolated nativesequence PRO983 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 243 of FIG. 109 (SEQ ID NO:284).Additional embodiments of the present invention are directed to PRO983polypeptides comprising amino acid 1 to X of FIG. 109 (SEQ ID NO:284),where X is any amino acid from 219 to 228 of FIG. 109 (SEQ ID NO:284).Optionally, the PRO983 polypeptide is obtained or is obtainable byexpressing the polypeptide encoded by the cDNA insert of theDNA53977-1371 vector deposited on May 14, 1998 as ATCC 209862.

[0524] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA17130 comprising thenucleotide sequence of FIG. 110 (SEQ ID NO:285).

[0525] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA23466 comprising thenucleotide sequence of FIG. 111 (SEQ ID NO:286).

[0526] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA26818 comprising thenucleotide sequence of FIG. 112 (SEQ ID NO:287).

[0527] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA37618 comprising thenucleotide sequence of FIG. 113 (SEQ ID NO:288).

[0528] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA41732 comprising thenucleotide sequence of FIG. 114 (SEQ ID NO:289).

[0529] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA45980 comprising thenucleotide sequence of FIG. 115 (SEQ ID NO:290).

[0530] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA46372 comprising thenucleotide sequence of FIG. 116 (SEQ ID NO:291).

[0531] 44. PRO1057

[0532] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to proteases, wherein the polypeptide isdesignated in the present application as “PRO1057”.

[0533] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO1057 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO1057polypeptide having amino acid residues 1 to 413 of FIG. 118 (SEQ IDNO:296), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO1057 polypeptide having amino acidresidues about 17 to 413 of FIG. 118 (SEQ ID NO:296), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA57253-1382 vector deposited on May 14, 1998 asATCC 209867 which includes the nucleotide sequence encoding PRO1057.

[0534] In another embodiment, the invention provides isolated PRO1057polypeptide. In particular, the invention provides isolated nativesequence PRO1057 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 413 of FIG. 118 (SEQ ID NO:296).Additional embodiments of the present invention are directed to PRO1057polypeptides comprising amino acids about 17 to 413 of FIG. 118 (SEQ IDNO:296). Optionally, the PRO1057 polypeptide is obtained or isobtainable by expressing the polypeptide encoded by the cDNA insert ofthe DNA57253-1382 vector deposited on May 14, 1998 as ATCC 209867.

[0535] 45. PRO1071

[0536] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to thrombospondin, wherein the polypeptideis designated in the present application as “PRO1071”.

[0537] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO1071 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO1071polypeptide having amino acid residues 1 to 525 of FIG. 120 (SEQ IDNO:301), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO1071 polypeptide having amino acidresidues about 26 to 525 of FIG. 120 (SEQ ID NO:301), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, aad optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA58847-1383 vector deposited on May 20, 1998 asATCC 209879 which includes the nucleotide sequence encoding PRO1071.

[0538] In another embodiment, the invention provides isolated PRO1071polypeptide. In particular, the invention provides isolated nativesequence PRO1071 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 525 of FIG. 120 (SEQ ID NO:301).Additional embodiments of the present invention are directed to PRO1071polypeptides comprising amino acids about 26 to 525 of FIG. 120 (SEQ IDNO:301). Optionally, the PRO1071 polypeptide is obtained or isobtainable by expressing the polypeptide encoded by the cDNA insert ofthe DNA58847-1383 vector deposited on May 20, 1998 as ATCC 209879.

[0539] 46. PRO1072

[0540] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to reductase proteins, wherein thepolypeptide is designated in the present application as “PRO1072”.

[0541] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO1072 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO1072polypeptide having amino acid residues 1 to 336 of FIG. 122 (SEQ IDNO:303), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO1072 polypeptide having amino acidresidues about 22 to 336 of FIG. 122 (SEQ ID NO:303), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA58747-1384 vector deposited on May 14, 1998 asATCC 209868 which includes the nucleotide sequence encoding PRO1072.

[0542] In another embodiment, the invention provides isolated PRO1072polypeptide. In particular, the invention provides isolated nativesequence PRO1072 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 336 of FIG. 122 (SEQ ID NO:303).Additional embodiments of the present invention are directed to PRO1072polypeptides comprising amino acids about 22 to 336 of FIG. 122 (SEQ IDNO:303). Optionally, the PRO1072 polypeptide is obtained or isobtainable by expressing the polypeptide encoded by the cDNA insert ofthe DNA58747-1384 vector deposited on May 14, 1998 as ATCC 209868.

[0543] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA40210 comprising thenucleotide sequence of FIG. 123 (SEQ ID NO:304).

[0544] 47. PRO1075

[0545] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to protein disulfide isomerase, wherein thepolypeptide is designated in the present application as “PRO1075”.

[0546] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO1075 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO1075polypeptide having amino acid residues 1 to 406 of FIG. 125 (SEQ IDNO:309), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO1075 polypeptide having amino acidresidues about 30 to 406 of FIG. 125 (SEQ ID NO:309), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA57689-1385 vector deposited on May 14, 1998 asATCC 209869 which includes the nucleotide sequence encoding PRO1075.

[0547] In another embodiment, the invention provides isolated PRO1075polypeptide. In particular, the invention provides isolated nativesequence PRO1075 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 406 of FIG. 125 (SEQ ID NO:309).Additional embodiments of the present invention are directed to PRO1075polypeptides comprising amino acids about 30 to 406 of FIG. 125 (SEQ IDNO:309). Optionally, the PRO1075 polypeptide is obtained or isobtainable by expressing the polypeptide encoded by the cDNA insert ofthe DNA57689-1385 vector deposited on May 14, 1998 as ATCC 209869.

[0548] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA13059 comprising thenucleotide sequence of FIG. 126 (SEQ ID NO:310).

[0549] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA19463 comprising thenucleotide sequence of FIG. 127 (SEQ ID NO:311).

[0550] 48. PRO181

[0551] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to the cornichon protein, wherein thepolypeptide is designated in the present application as “PRO181”.

[0552] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO181 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO181polypeptide having amino acid residues 1 to 144 of FIG. 129 (SEQ IDNO:322), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO181 polypeptide having amino acidresidues about 21 to 144 of FIG. 129 (SEQ ID NO:322) or amino acid 1 orabout 21 to X of FIG. 129 (SEQ ID NO:322) where X is any amino acid from52 to 61 of FIG. 129 (SEQ ID NO:322), or is complementary to suchencoding nucleic acid sequence, and remains stably bound to it under atleast moderate, and optionally, under high stringency conditions. Theisolated nucleic acid sequence may comprise the cDNA insert of theDNA23330-1390 vector deposited on Apr. 14, 1998 as ATCC 209775 whichincludes the nucleotide sequence encoding PRO181.

[0553] In another embodiment, the invention provides isolated PRO181polypeptide. In particular, the invention provides isolated nativesequence PRO181 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 144 of FIG. 129 (SEQ ID NO:322).Additional embodiments of the present invention are directed to PRO181polypeptides comprising amino acids about 21 to 144 of FIG. 129 (SEQ IDNO:322) or amino acid 1 or about 21 to X of FIG. 129 (SEQ ID NO:322),where X is any amino acid from 52 to 61 of FIG. 129 (SEQ ID NO:322).Optionally, the PRO181 polypeptide is obtained or is obtainable byexpressing the polypeptide encoded by the cDNA insert of theDNA23330-1390 vector deposited on Apr. 14, 1998 as ATCC 209775.

[0554] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA13242 comprising thenucleotide sequence of FIG. 130 (SEQ ID NO:323).

[0555] 49. PRO195

[0556] Applicants have identified a cDNA clone that encodes a noveltransmembrane polypeptide, wherein the polypeptide is designated in thepresent application as “PRO195”.

[0557] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO195 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO195polypeptide having amino acid residues 1 to 323 of FIG. 132 (SEQ IDNO:330), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO195 polypeptide having amino acidresidues about 32 to 323 of FIG. 132 (SEQ ID NO:330) or amino acid 1 orabout 32 to X of FIG. 132 (SEQ ID NO:330) where X is any amino acid from236 to 245 of FIG. 132 (SEQ ID NO:330), or is complementary to suchencoding nucleic acid sequence, and remains stably bound to it under atleast moderate, and optionally, under high stringency conditions. Theisolated nucleic acid sequence may comprise the cDNA insert of theDNA26847-1395 vector deposited on Apr. 14, 1998 as ATCC 209772 whichincludes the nucleotide sequence encoding PRO195.

[0558] In another embodiment, the invention provides isolated PRO195polypeptide. In particular, the invention provides isolated nativesequence PRO195 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 323 of FIG. 132 (SEQ ID NO:330).Additional embodiments of the present invention are directed to PRO195polypeptides comprising amino acids about 32 to 323 of FIG. 132 (SEQ IDNO:330) or amino acid 1 or about 32 to X of FIG. 132 (SEQ ID NO:330),where X is any amino acid from 236 to 245 of FIG. 132 (SEQ ID NO:330).Optionally, the PRO195 polypeptide is obtained or is obtainable byexpressing the polypeptide encoded by the cDNA insert of theDNA26847-1395 vector deposited on Apr. 14, 1998 as ATCC 209772.

[0559] In another embodiment, the invention provides an expressedsequence tag (EST) comprising the nucleotide sequence of FIG. 133 (SEQID NO:331), herein designated DNA15062.

[0560] In another embodiment, the invention provides an expressedsequence tag (EST) comprising the nucleotide sequence of FIG. 134 (SEQID NO:332), herein designated DNA13199.

[0561] 50. PRO865

[0562] Applicants have identified a cDNA clone that encodes a novelsecreted polypeptide, wherein the polypeptide is designated in thepresent application as “PRO865”.

[0563] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO865 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO865polypeptide having amino acid residues 1 to 468 of FIG. 136 (SEQ IDNO:337), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO865 polypeptide having amino acidresidues about 24 to 229 of FIG. 136 (SEQ ID NO:337), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA53974-1401 vector deposited on Apr. 14, 1998as ATCC 209774 which includes the nucleotide sequence encoding PRO865.

[0564] In another embodiment, the invention provides isolated PRO865polypeptide. In particular, the invention provides isolated nativesequence PRO865 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 468 of FIG. 136 (SEQ ID NO:337).An additional embodiment of the present invention is directed to aPRO865 polypeptide comprising amino acids about 24 to 468 of FIG. 136(SEQ ID NO:337). Optionally, the PRO865 polypeptide is obtained or isobtainable by expressing the polypeptide encoded by the cDNA insert ofthe DNA53974-1401 vector deposited on Apr. 14, 1998 as ATCC 209774.

[0565] In another embodiment, the invention provides an expressedsequence tag (EST) comprising the nucleotide sequence of FIG. 137 (SEQID NO:338), herein designated as DNA37642.

[0566] 51. PRO827

[0567] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to integrin proteins, wherein thepolypeptide is designated in the present application as “PRO827”.

[0568] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO827 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO827polypeptide having amino acid residues 1 to 124 of FIG. 139 (SEQ IDNO:346), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO827 polypeptide having amino acidresidues about 23 to 124 of FIG. 139 (SEQ ID NO:346), or iscomplementary to such encoding nucleic acid sequence, and remains stablybound to it under at least moderate, and optionally, under highstringency conditions. The isolated nucleic acid sequence may comprisethe cDNA insert of the DNA57039-1402 vector deposited on Apr. 14, 1998as ATCC 209777 which includes the nucleotide sequence encoding PRO827.

[0569] In another embodiment, the invention provides isolated PRO827polypeptide. In particular, the invention provides isolated nativesequence PRO827 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 to 124 of FIG. 139 (SEQ ID NO:346).An additional embodiment of the present invention is directed to aPRO827 polypeptide comprising amino acids about 23 to 124 of FIG. 139(SEQ ID NO:346). Optionally, the PRO827 polypeptide is obtained or isobtainable by expressing the polypeptide encoded by the cDNA insert ofthe DNA57039-1402 vector deposited on Apr. 14, 1998 as ATCC 209777.

[0570] 52. PRO1114

[0571] Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to cytokine receptor family-4 proteins,wherein the polypeptide is designated in the present application as“PRO1114”.

[0572] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO1114 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO1114polypeptide having amino acid residues 1 to 311 of FIG. 142 (SEQ IDNO:352), or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions. In other aspects, the isolated nucleicacid comprises DNA encoding the PRO1114 polypeptide having amino acidresidues about 30 to 311 of FIG. 142 (SEQ ID NO:352) or amino acid 1 orabout 30 to X of FIG. 142 (SEQ ID NO:352), where X is any amino acidfrom 225 to 234 of FIG. 142 (SEQ ID NO:352), or is complementary to suchencoding nucleic acid sequence, and remains stably bound to it under atleast moderate, and optionally, under high stringency conditions. Theisolated nucleic acid sequence may comprise the cDNA insert of theDNA57033-1403 vector deposited on May 27, 1998 as ATCC 209905 whichincludes the nucleotide sequence encoding PRO1114.

[0573] In another embodiment, the invention provides isolated PRO1114polypeptide. In particular, the invention provides isolated nativesequence PRO11114 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 311 of FIG. 142 (SEQ IDNO:352). Additional embodiments of the present invention are directed toPRO1114 polypeptides comprising amino acids about 30 to 311 of FIG. 142(SEQ ID NO:352) or amino acid 1 or about 30 to X of FIG. 142 (SEQ IDNO:352), where X is any amino acid from 225 to 234 of FIG. 142 (SEQ IDNO:352). Optionally, the PRO1114 polypeptide is obtained or isobtainable by expressing the polypeptide encoded by the cDNA insert ofthe DNA57033-1403 vector deposited on May 27, 1998 as ATCC 209905.

[0574] In another embodiment, the invention provides an expressedsequence tag (EST) designated herein as DNA48466 comprising thenucleotide sequence of FIG. 143 (SEQ ID NO:353).

[0575] A cDNA clone (DNA57033-1403) has been identified that encodes anovel interferon receptor polypeptide, designated in the presentapplication as “PRO1114 interferon receptor”.

[0576] In one embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO1114 interferon receptorpolypeptide.

[0577] In one aspect, the isolated nucleic acid comprises DNA having atleast about 80% sequence identity, preferably at least about 85%sequence identity, more preferably at least about 90% sequence identity,most preferably at least about 95% sequence identity to (a) a DNAmolecule encoding a PRO1114 interferon receptor polypeptide having thesequence of amino acid residues from about 1 or about 30 to about 311,inclusive of FIG. 142 (SEQ ID NO:352), or (b) the complement of the DNAmolecule of (a).

[0578] In another aspect, the invention concerns an isolated nucleicacid molecule encoding a PRO1114 interferon receptor polypeptidecomprising DNA hybridizing to the complement of the nucleic acid betweenabout nucleotides 250 or about 337 and about 1182, inclusive, of FIG.141 (SEQ ID NO:351). Preferably, hybridization occurs under stringenthybridization and wash conditions.

[0579] In a further aspect, the invention concerns an isolated nucleicacid molecule comprising DNA having at least about 80% sequenceidentity, preferably at least about 85% sequence identity, morepreferably at least about 90% sequence identity, most preferably atleast about 95% sequence identity to (a) a DNA molecule encoding thesame mature polypeptide encoded by the human protein cDNA in ATCCDeposit No. 209905 (DNA57033-1403) or (b) the complement of the nucleicacid molecule of (a). In a preferred embodiment, the nucleic acidcomprises a DNA encoding the same mature polypeptide encoded by thehuman protein cDNA in ATCC Deposit No. 209905 (DNA57033-1403).

[0580] In still a further aspect, the invention concerns an isolatednucleic acid molecule comprising (a) DNA encoding a polypeptide havingat least about 80% sequence identity, preferably at least about 85%sequence identity, more preferably at least about 90% sequence identity,most preferably at least about 95% sequence identity to the sequence ofamino acid residues 1 or about 30 to about 311, inclusive of FIG. 142(SEQ ID NO:352), or (b) the complement of the DNA of (a).

[0581] In a further aspect, the invention concerns an isolated nucleicacid molecule having at least 10 nucleotides and produced by hybridizinga test DNA molecule under stringent conditions with (a) a DNA moleculeencoding a PRO1114 interferon receptor polypeptide having the sequenceof amino acid residues from 1 or about 30 to about 311, inclusive ofFIG. 142 (SEQ ID NO:352), or (b) the complement of the DNA molecule of(a), and, if the DNA molecule has at least about an 80% sequenceidentity, prefereably at least about an 85% sequence identity, morepreferably at least about a 90% sequence identity, most preferably atleast about a 95% sequence identity to (a) or (b), isolating the testDNA molecule.

[0582] In a specific aspect, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO1114 interferon receptorpolypeptide, with or without the N-terminal signal sequence and/or theinitiating methionine, and its soluble, i.e., transmembrane domaindeleted or inactivated variants, or is complementary to such encodingnucleic acid molecule. The signal peptide has been tentativelyidentified as extending from about amino acid position 1 to about aminoacid position 29 in the sequence of FIG. 142 (SEQ ID NO:352). Thetransmembrane domain has been tentatively identified as extending fromabout amino acid position 230 to about amino acid position 255 in thePRO1114 interferon receptor amino acid sequence (FIG. 142, SEQ IDNO:352).

[0583] In another aspect, the invention concerns an isolated nucleicacid molecule comprising (a) DNA encoding a polypeptide scoring at leastabout 80% positives, preferably at least about 85% positives, morepreferably at least about 90% positives, most preferably at least about95% positives when compared with the amino acid sequence of residues 1or about 30 to about 311, inclusive of FIG. 142 (SEQ ID NO:352), or (b)the complement of the DNA of (a).

[0584] Another embodiment is directed to fragments of a PRO1114interferon receptor polypeptide coding sequence that may find use ashybridization probes. Such nucleic acid fragments are from about 20 toabout 80 nucleotides in length, preferably from about 20 to about 60nucleotides in length, more preferably from about 20 to about 50nucleotides in length and most preferably from about 20 to about 40nucleotides in length and may be derived from the nucleotide sequenceshown in FIG. 141 (SEQ ID NO:351).

[0585] In another embodiment, the invention provides a vector comprisingDNA encoding PRO1114 interferon receptor or its variants. The vector maycomprise any of the isolated nucleic acid molecules hereinaboveidentified.

[0586] A host cell comprising such a vector is also provided. By way ofexample, the host cells may be CHO cells, E. coli, or yeast. A processfor producing PRO1114 interferon receptor polypeptides is furtherprovided and comprises culturing host cells under conditions suitablefor expression of PRO1114 interferon receptor and recovering PRO1114interferon receptor from the cell culture.

[0587] In another embodiment, the invention provides isolated PRO1114interferon receptor polypeptide encoded by any of the isolated nucleicacid sequences hereinabove identified.

[0588] In a specific aspect, the invention provides isolated nativesequence PRO1114 interferon receptor polypeptide, which in certainembodiments, includes an amino acid sequence comprising residues 1 orabout 30

58. (New) An antibody that binds to the polypeptide shown in FIG. 49(SEQ ID NO:132).
 59. (New) The antibody of claim 58 which is amonoclonal antibody.
 60. (New) The antibody of claim 58 which is ahumanized antibody.
 61. (New) The antibody of claim 58 which is anantibody fragment.
 62. (New) The antibody of claim 58 which is labeled.63. (New) The antibody of claim 58 which specifically binds to thepolypeptide shown FIG. 49 (SEQ ID NO:132).